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Zhu X, Xiong C, Zhou H, Wang J, Wu Y. Single-atom nanozymes for enhanced electrochemical biosensing: A review. Talanta 2025; 294:128179. [PMID: 40286743 DOI: 10.1016/j.talanta.2025.128179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/30/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025]
Abstract
Enzyme-based electrochemical biosensors have broad and significant applications in biomedical, environmental monitoring, and food safety fields. However, the application of natural enzymes is limited due to issues such as poor stability, complex preparation, and high cost. Single-atom nanozymes (SAzymes), with their unique catalytic properties and efficient enzyme-like activities, present a promising alternative in the field of electrochemical biosensing. Compared to traditional enzymes, SAzyme offer enhanced stability and controllability, making them particularly effective in complex detection environments. This work presents the first systematic review of the progress made since 2018 in the use of SAzymes as alternatives to natural enzymes in electrochemical biosensors, and presents the latest advancements in this area. The review begins with a discussion of various enzyme-like activities of single-atom materials, including peroxidase (POD)-like, oxidase (OXD)-like, catalase (CAT)-like, and superoxide dismutase (SOD)-like activities. It then explores the advantages of SAzymes in improving the performance of electrochemical biosensors from multiple perspectives. The review also summarizes the applications of SAzyme-based electrochemical sensors for reactive oxygen species (ROS), metabolites, neurotransmitters, and other analytes, highlighting specific examples to elucidate underlying catalytic mechanisms and understand fundamental structure-performance relationships. In the final section, the challenges faced by SAzyme-based electrochemical biosensing are discussed, along with potential solutions.
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Affiliation(s)
- Xiaofei Zhu
- College of Materials Science and Engineering, Shenzhen University, Shenzhen, 518071, China; Key Laboratory of Precision and Intelligent/School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230026, China
| | - Can Xiong
- Key Laboratory of Precision and Intelligent/School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230026, China
| | - Huang Zhou
- Key Laboratory of Precision and Intelligent/School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230026, China
| | - Jin Wang
- College of Materials Science and Engineering, Shenzhen University, Shenzhen, 518071, China.
| | - Yuen Wu
- Key Laboratory of Precision and Intelligent/School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230026, China; Deep Space Exploration Laboratory/School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230026, China.
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2
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Zhou QM, Lu YF, Yang XY, Zhang JG, Wang YN, Luo WP, Mao J, Hou J, Wu F, Wang WL, Tang GP, Bai HZ, Yu RS. Redox-driven hybrid nanoenzyme dynamically activating ferroptosis and disulfidptosis for hepatocellular carcinoma theranostics. J Colloid Interface Sci 2025; 693:137611. [PMID: 40253866 DOI: 10.1016/j.jcis.2025.137611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 04/14/2025] [Accepted: 04/15/2025] [Indexed: 04/22/2025]
Abstract
Hepatocellular carcinoma (HCC) presents formidable therapeutic challenges due to its pronounced metabolic heterogeneity, particularly arising from spatially uneven glucose availability within the tumor microenvironment (TME). To address this, we developed a glutathione (GSH)-responsive, biomimetic hybrid nanoenzyme system (M@GOx/Fe-HMON) composed of hollow mesoporous organosilica nanoparticles co-loaded with glucose oxidase (GOx) and Fe2+/Fe3+ redox pairs, and cloaked in homologous tumor cell membranes for enhanced targeting. In glucose-rich regions, the nanoenzyme orchestrates a GOx-peroxidase (POD) cascade that produces reactive oxygen species (ROS) via the Fenton reaction, leading to ferroptosis through intensified oxidative stress and GSH depletion. Conversely, under glucose-deficient conditions, the nanoenzyme promotes disulfidptosis by aggravating glucose deprivation, depleting nicotinamide adenine dinucleotide phosphate (NADPH), and impairing cystine metabolism, ultimately resulting in actin cytoskeletal collapse. This dual-action platform dynamically adapts to the tumor's metabolic landscape, selectively inducing ferroptosis or disulfidptosis according to glucose levels, disrupting redox homeostasis and amplifying antitumor efficacy. Notably, this study is the first to integrate ferroptosis and disulfidptosis activation into a single, metabolism-sensitive nanoenzyme system, providing a novel paradigm for exploiting tumor metabolic heterogeneity. Furthermore, the combination of endogenous metabolic regulation with magnetic resonance imaging (MRI)-guided diagnosis introduces an innovative and noninvasive strategy for precision cancer theranostics.
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Affiliation(s)
- Qiao-Mei Zhou
- Department of Radiology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, PR China
| | - Yuan-Fei Lu
- Department of Radiology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, PR China
| | - Xiao-Yan Yang
- Department of Radiology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, PR China
| | - Jin-Guo Zhang
- Department of Radiology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, PR China
| | - Yi-Ning Wang
- Department of Radiology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, PR China
| | - Wang-Ping Luo
- Department of Radiology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, PR China
| | - Jin Mao
- Department of Radiology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, PR China
| | - Jue Hou
- Department of Chemistry, Zhejiang University, Hangzhou 310058, PR China
| | - Fan Wu
- Department of Neurosurgery, The First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, PR China
| | - Wei-Lin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, PR China
| | - Gu-Ping Tang
- Department of Chemistry, Zhejiang University, Hangzhou 310058, PR China.
| | - Hong-Zhen Bai
- Department of Chemistry, Zhejiang University, Hangzhou 310058, PR China.
| | - Ri-Sheng Yu
- Department of Radiology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, PR China.
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Shen T, Wang Y, Cheng L, Bode AM, Gao Y, Zhang S, Chen X, Luo X. Oxidative complexity: The role of ROS in the tumor environment and therapeutic implications. Bioorg Med Chem 2025; 127:118241. [PMID: 40383035 DOI: 10.1016/j.bmc.2025.118241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 05/01/2025] [Accepted: 05/12/2025] [Indexed: 05/20/2025]
Abstract
Reactive oxygen species (ROS) constitutes a group of reactive molecules that play a critical role in biological processes. Varying ROS levels have been frequently observed in cancer cells and the tumor microenvironment (TME). The role of ROS displays significant complexity in cancer development and therapy. Elevated ROS levels can induce metabolic reprogramming and promote the proliferation, invasion, and metastasis of cancer cells, resulting in cancer progression. However, excessive ROS accumulation leads to the occurrence of apoptosis, pyroptosis, necroptosis, and ferroptosis in cancer cells, which restrains tumor development. In the TME, ROS frequently promotes angiogenesis and remodels the extracellular matrix (ECM) by enhancing the differentiation of cancer-associated fibroblasts (CAFs), thereby supporting tumor growth. Concurrently, high ROS levels favour immunosuppressive cells, including M2-polarized macrophages, and regulatory T cells (Tregs), while impairing the antitumor capabilities of T cells. In the aspect of cancer therapy, it is overly simplistic to merely combine chemoradiotherapy with antioxidants as a therapeutic strategy. Instead, highlighting targeted therapies that modulate ROS is essential, given their inherent complexity. Fortunately, a variety of innovative treatments have emerged, including nanodrug delivery systems (NDDS), proteolysis-targeting chimeras (PROTAC), and adoptive cell therapy (ADT), which not only exhibit synergistic effects with immune checkpoint therapy (ICT), but also enhance the antitumor capabilities of the TME. In this paper, we elucidate the mechanism of ROS production, enumerate the role of ROS in cancer development and the TME, and discuss advancements in ROS-targeted cancer therapeutics.
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Affiliation(s)
- Tingfeng Shen
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Yutong Wang
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Linmao Cheng
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
| | - Ya Gao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Shuntong Zhang
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Xue Chen
- Early Clinical Trial Center, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Xiangjian Luo
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410078, China.
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4
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Shao Z, Zeng J, Dong J, Ji F, Li H, Yang R, Chen W, Li W, Wang S. An integrated non-alkaline derivatization strategy using 2,2'-dithiodipyridine and HPLC for simultaneous analysis of total and low-molecular-weight free thiols in human serum. Anal Chim Acta 2025; 1358:344078. [PMID: 40374240 DOI: 10.1016/j.aca.2025.344078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 04/02/2025] [Accepted: 04/14/2025] [Indexed: 05/17/2025]
Abstract
BACKGROUND Oxidative stress is a major mechanism underlying aging and health damage, and it is associated with decreased serum free thiol levels. Monitoring serum free thiol levels provides a valuable reference for assessing the body's health status. However, it is a key challenge in clinical analysis to simultaneously monitor serum total free thiols and specific low-molecular-mass free thiol compounds in a single run. Traditional methods often struggle to avoid interference from side reactions due to the high reactivity of free thiols in alkaline derivatization environments. RESULTS In this study, we developed an integrated non-alkaline derivatization strategy using 2,2'-dithiodipyridine and high-performance liquid chromatography. 2,2'-Dithiodipyridine can react rapidly with free thiols under acidic to neutral environments, and all derivatives exhibit similar absorbance characteristics to the substrates. Taking advantage of these properties, this method combines reliable derivatization with efficient chromatographic separation, enabling the simultaneous analysis of total free thiols and five main specific low-molecular-mass thiol compounds within a single injection cycle. Eight chromatographic peaks including free thiol derivatives, the derivatization reagent, and internal standard were observed during a 14-min analysis. The peak corresponding to 2-thiopyridone indicates the total concentration of free thiols while specific pyridyldithio derivative peaks represent the individual levels of low-molecular-mass free thiols. Using the developed method, a significant negative correlation was observed between free thiol levels and both age and health risk factors in a study involving 260 volunteers. SIGNIFICANCE This study presents a robust and simple method for the simultaneous measurement of total free and low-molecular-mass free thiols, providing a facile technique for population analysis and for investigating the relationship between free thiols and human health.
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Affiliation(s)
- Zhiyu Shao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, NO.1 Da Hua Road, Dong Dan, Beijing, 100730, PR China
| | - Jie Zeng
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, NO.1 Da Hua Road, Dong Dan, Beijing, 100730, PR China
| | - Jun Dong
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, NO.1 Da Hua Road, Dong Dan, Beijing, 100730, PR China
| | - Fusui Ji
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, NO.1 Da Hua Road, Dong Dan, Beijing, 100730, PR China
| | - Hongxia Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, NO.1 Da Hua Road, Dong Dan, Beijing, 100730, PR China
| | - Ruiyue Yang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, NO.1 Da Hua Road, Dong Dan, Beijing, 100730, PR China
| | - Wenxiang Chen
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, NO.1 Da Hua Road, Dong Dan, Beijing, 100730, PR China
| | - Wenyu Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, NO.1 Da Hua Road, Dong Dan, Beijing, 100730, PR China
| | - Siming Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, NO.1 Da Hua Road, Dong Dan, Beijing, 100730, PR China.
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Hu M, Wang F, Zhu Y, Yao Y, Pei H, Liu Z, Zhang P. NADK tetramer defective mutants affect lung cancer response to chemotherapy via controlling NADK activity. Genes Dis 2025; 12:101510. [PMID: 40330153 PMCID: PMC12052686 DOI: 10.1016/j.gendis.2024.101510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/25/2024] [Accepted: 12/18/2024] [Indexed: 05/08/2025] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) kinase (NADK) phosphorylates NAD+ to generate NADP+, which plays a crucial role in maintaining NAD+/NADP+ homeostasis, cellular redox balance, and metabolism. However, how human NADK activity is regulated, and how dysregulation or mutation of NADK is linked to human diseases, such as cancers, are still not fully understood. Here, we present a cryo-EM structure of human tetrameric NADK and elaborate on the necessity of the NADK tetramer for its activity. The N-terminal region of human NADK, which does not exist in bacterial NADKs, modulates tetramer conformation, thereby regulating its activity. A methylation-deficient mutant, R45H, within the N-terminal region results in increased NADK activity and confers cancer chemotherapy resistance. Conversely, mutations in NADK identified among cancer patients alter the tetramer conformation, resulting in NADK inactivation and increasing the sensitivity of lung cancer cells to chemotherapy. Our findings partially unveil the structural basis for NADK regulation, offering insights into the cancer etiology of patients carrying NADK mutations.
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Affiliation(s)
- Mengxue Hu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Fuxing Wang
- School of Medicine, Kobilka Institute of Innovative Drug Discovery, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong 518172, China
| | - Yue Zhu
- Department of Radiotherapy, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Yi Yao
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Huadong Pei
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Zheng Liu
- School of Medicine, Kobilka Institute of Innovative Drug Discovery, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong 518172, China
| | - Pingfeng Zhang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
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Huang Z, Li A, Huang R, Shi M, Yang R, Wang W, Huang Z, Liu Y, Wu J. Effect of xylitol on low‑density lipoprotein‑stimulated oxidative stress in THP‑1 cells. Mol Med Rep 2025; 32:190. [PMID: 40341459 PMCID: PMC12076051 DOI: 10.3892/mmr.2025.13555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 04/03/2025] [Indexed: 05/10/2025] Open
Abstract
Atherosclerosis (AS) is a chronic inflammatory disease caused by oxidative stress and the oxidation of low‑density lipoprotein (LDL). Xylitol, a widely used sugar substitute, has antioxidant potential; however, its effects on LDL‑induced oxidative stress in AS remain unclear. Using western blot, reverse transcription‑quantitative PCR, flow cytometry and so on, the present study investigated the role of xylitol in mitigating oxidative stress induced by high levels of LDL in Tohoku Hospital Pediatrics‑1 (THP‑1) human monocytic cell line), a model for studying AS. Xylitol significantly alleviated high LDL‑induced oxidative stress in THP‑1 cells and decreased reactive oxygen species levels, malondialdehyde content and the expression of NADPH oxidase family enzymes. Concurrently, xylitol enhanced the activity and expression of superoxide dismutase and increased the glutathione levels. Mechanistically, xylitol activated the nuclear factor erythroid 2‑related factor 2 (Nrf2)/heme oxygenase‑1 (HO‑1) axis by increasing the NADPH/NADP+ ratio via the regulation of the pentose phosphate pathway via the Nrf2 transcription factor. This led to a decrease in LDL oxidative modification in THP‑1 cells (Figs. 6,7). Overall, xylitol attenuates high LDL level‑induced oxidative stress in THP‑1 cells by modulating the Nrf2‑mediated pentose phosphate pathway and activating the Nrf2/HO‑1 axis, highlighting its potential for the prevention and treatment of AS.
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Affiliation(s)
- Zile Huang
- Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430072, P.R. China
| | - Anke Li
- Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430072, P.R. China
| | - Rui Huang
- Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Mengmeng Shi
- Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430072, P.R. China
| | - Rujing Yang
- Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430072, P.R. China
| | - Wenyan Wang
- Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430072, P.R. China
| | - Zhen Huang
- Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430072, P.R. China
| | - Yanhong Liu
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Junzhu Wu
- Taikang Medical School, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430072, P.R. China
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Hellmann ZJ, Rehman S, Brown LM, Vasquez JC, Solomon DG, Christison-Lagay ER. Relationship Between Total Parenteral Nutrition, Ventilation, and Hepatoblastoma: A Study of 258,929 Neonatal Intensive Care Unit Admissions. Pediatr Blood Cancer 2025; 72:e31741. [PMID: 40275525 DOI: 10.1002/pbc.31741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 03/09/2025] [Accepted: 04/09/2025] [Indexed: 04/26/2025]
Abstract
INTRODUCTION Gestational age, low birth weight, and overgrowth syndromes are associated with the diagnosis of hepatoblastoma. Previous studies have come to mixed conclusions regarding the contribution of other neonatal intensive care unit (NICU) exposures to hepatoblastoma development. We hypothesized that total parenteral nutrition (TPN) and mechanical ventilation during index NICU admission would correlate with the development of hepatoblastoma. METHODS The Pediatric Health Information System (PHIS) was queried for all infants admitted to the NICU with birthdates between 2016 and 2022. From this set, patients subsequently admitted to a PHIS hospital between 2016 and 2023 with a diagnosis code for hepatoblastoma were identified. Billing information was used to calculate the number of days of TPN and mechanical ventilation exposure during NICU hospitalization. RESULTS A total of 258,929 patients were included, with 51 patients diagnosed with hepatoblastoma. Patients with any duration of TPN (OR = 8.51, 95% CI 4.00-18.09) or mechanical ventilation (OR = 8.21, 95% CI 4.30-15.69) developed hepatoblastoma more frequently. Matched conditional logistic regression, on gestational age and birth weight, showed a significant increase in hepatoblastoma for each additional 10 days of TPN (OR = 1.25, 95% CI 1.06-1.50) and mechanical ventilation (OR = 1.21, 95% CI 1.06-1.39). DISCUSSION Leveraging the magnitude of the PHIS, we were able to demonstrate a significant relationship between the duration of exposure to both TPN and mechanical ventilation and the later diagnosis of hepatoblastoma. Although the PHIS lacks granularity in reporting clinical characteristics (e.g., mode and concentration of oxygen delivery and composition of TPN) of these common NICU interventions, future investigations should be directed at the role they may play in hepatoblastoma oncogenesis.
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Affiliation(s)
- Zane J Hellmann
- Division of Pediatric Surgery, Yale New Haven Children's Hospital, New Haven, Connecticut, USA
| | - Shahyan Rehman
- Division of Pediatric Surgery, Yale New Haven Children's Hospital, New Haven, Connecticut, USA
| | - Leanne M Brown
- Division of Pediatric Surgery, Yale New Haven Children's Hospital, New Haven, Connecticut, USA
| | - Juan C Vasquez
- Division of Pediatric Hematology and Oncology, Yale New Haven Children's Hospital, New Haven, Connecticut, USA
| | - Daniel G Solomon
- Division of Pediatric Surgery, Yale New Haven Children's Hospital, New Haven, Connecticut, USA
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MacMillan AC, Karki B, Yang J, Gertz KR, Zumwalde S, Patel JG, Czyzyk-Krzeska MF, Meller J, Cunningham JT. PRPS activity tunes redox homeostasis in Myc-driven lymphoma. Redox Biol 2025; 84:103649. [PMID: 40446642 PMCID: PMC12166406 DOI: 10.1016/j.redox.2025.103649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Accepted: 04/21/2025] [Indexed: 06/18/2025] Open
Abstract
Myc hyperactivation coordinately regulates numerous metabolic processes to drive lymphomagenesis. Here, we elucidate the temporal and functional relationships between the medley of pathways, factors, and mechanisms that cooperate to control redox homeostasis in Myc-overexpressing B cell lymphomas. We find that Myc overexpression rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleotide synthesis, and mitochondrial respiration, which collectively steers cellular equilibrium to a more oxidative state. We identify Myc-dependent hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme as a primary regulator of redox status in lymphoma cells. Mechanistically, we show that genetic inactivation of the PRPS2 isozyme, but not PRPS1, in Myc-driven lymphoma cells leads to elevated NADPH levels and reductive stress-mediated death. Employing a pharmacological screen, we demonstrate how targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance, respectively, to chemotherapeutic agents affecting the thioredoxin and glutathione network, thus providing a therapeutic blueprint for treating Myc-driven lymphomas.
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Affiliation(s)
- Austin C MacMillan
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Bibek Karki
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Juechen Yang
- Department of Biostatistics, Health Informatics and Data Sciences, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Karmela R Gertz
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Samantha Zumwalde
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Jay G Patel
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Maria F Czyzyk-Krzeska
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Veteran Affairs Medical Center, Department of Veterans Affairs, Cincinnati, OH, 45220, USA; Department of Pharmacology and System Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Jarek Meller
- Department of Biostatistics, Health Informatics and Data Sciences, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Institute of Engineering and Technology, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University, Torun, 87-100, Poland
| | - John T Cunningham
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
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Lu L, Tao R. Prognostic implications of glucose metabolism pathways in colon adenocarcinoma: a comprehensive outlook on the molecular landscape and immunotherapy. Biochem Biophys Res Commun 2025; 768:151961. [PMID: 40345006 DOI: 10.1016/j.bbrc.2025.151961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/30/2025] [Accepted: 05/05/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND Colon adenocarcinoma (COAD) is a common and aggressive cancer characterized by significant metabolic alterations, particularly in glucose metabolism. Identifying key genes and pathways involved in glucose metabolism could provide valuable prognostic biomarkers and therapeutic targets. METHODS Clinical and transcriptomic data for patients with COAD were obtained from TCGA and validated using external datasets (GSE17536 and GSE39582). Seventeen glucose metabolism-related pathways were selected from the MSigDB and analysed using ssGSEA. WGCNA was used to identify key gene modules. Prognostic genes were selected via univariate Cox regression, Lasso-Cox regression, and multivariate Cox regression. Model validation was conducted using independent datasets. Immunotherapy prediction and immune infiltration analyses were also performed. A-NEK9 knockdown cell line was established using SW1116 and SW480 cell lines. The effect of NEK9 on COAD was evaluated in vivo and in vitro. The effects of NEK9 on glucose uptake and lactate production were also assessed. RESULTS A prognostic model based on five glucose metabolism-related genes (NEK9, HS2ST1, AC016394.3, H2BC21, and MIR23A) was developed. The model demonstrated strong predictive value, with high-risk patients showing poorer survival outcomes in both the TCGA and external validation cohorts. Additionally, lower risk scores were associated with better responses to immunotherapy, as indicated by TIDE and SubMap analyses. These findings were further validated through ROC analysis, which revealed robust predictive performance for immunotherapy response across multiple cohorts. NEK9 promoted the proliferation and tumour angiogenesis of SW1116 and SW480 cells, inhibited apoptosis, and enhanced glucose uptake and lactate production in tumour cells. NEK9 knockdown significantly inhibited the tumorigenic ability of COAD in mice. CONCLUSIONS This study highlights the role of glucose metabolism in COAD and presents a novel prognostic model based on glucose metabolism-related genes. The model has potential clinical applications for predicting survival and guiding immunotherapy decisions in patients with COAD.
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Affiliation(s)
- Ling Lu
- Medical College of Soochow University, Suzhou, Jiangsu, 215123, China; Center for Rehabilitation Medicine Center, Department of Anesthesiology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Ran Tao
- Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
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10
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Duan D, Yang X, Guo X, Li M, Jin X, Wang L, Xiao J, Wang X, Song P. Interaction of glaucocalyxin a with glutathione and thioredoxin reductase for triple-negative breast cancer treatment. Bioorg Chem 2025; 161:108572. [PMID: 40359839 DOI: 10.1016/j.bioorg.2025.108572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/15/2025]
Abstract
Glaucocalyxin A (GLA) is a bioactive diterpenoid isolated from Rabdosia japonica var. that has been applied for centuries in traditional Chinese medicine. Although GLA exhibits potent anticancer activity against various human cancer cells, its cellular targets remain largely unidentified. We reported here that GLA covalently modifies glutathione and selectively inhibits TrxR activity by primarily targeting the Sec498 residue of the protein. Pharmacologic inhibition of TrxR with GLA results in accumulation of reactive oxygen species, decreased total glutathione and thiols, collapse of the intracellular redox balance, and eventually induction of oxidative stress mediated apoptosis in triple-negative breast cancer cells. Importantly, knockdown of TrxR1 increases the sensitivity cells to GLA. Targeting TrxR by GLA thus discloses a newly identified molecular mechanism underlying the biological activity of GLA, and provides an in-depth insight in understanding the action of GLA in treatment of cancer.
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Affiliation(s)
- Dongzhu Duan
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China.
| | - Xing Yang
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China
| | - Xiangyu Guo
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China
| | - Mi Li
- School of Pharmacy, Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, and Affiliated Hospital of Gansu University of Chinese Medicine and Key Laboratory of Prevention and Treatment for Chronic Diseases by TCM, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Xiaojie Jin
- School of Pharmacy, Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, and Affiliated Hospital of Gansu University of Chinese Medicine and Key Laboratory of Prevention and Treatment for Chronic Diseases by TCM, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Le Wang
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China
| | - Jian Xiao
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China
| | - Xiaoling Wang
- Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China.
| | - Peng Song
- School of Pharmacy, Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, and Affiliated Hospital of Gansu University of Chinese Medicine and Key Laboratory of Prevention and Treatment for Chronic Diseases by TCM, Gansu University of Chinese Medicine, Lanzhou 730000, China.
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11
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Mao Y, Liu X, Chu X, Chen F, Shi R, Liu Z, Wu Y, Liu Y, Bu W. Nanomedicine-Driven Modulation of Reductive Stress for Cancer Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e01968. [PMID: 40569215 DOI: 10.1002/advs.202501968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 05/26/2025] [Indexed: 06/28/2025]
Abstract
Redox balance is crucial for cellular function and adaptation to environmental changes, with its disruption playing a key role in the progression of various diseases, including cancer. While oxidative stress caused by excessive reactive oxygen species (ROS) has been widely studied and targeted in cancer therapies, such approaches face significant challenges within the tumor microenvironment. On the opposite end, reductive stress results from an overabundance of reducing equivalents, disrupting normal ROS-dependent signaling pathways and leading to cellular dysfunction. Despite its importance in tumor biology, reductive stress has received less attention than oxidative stress. This group has deliberately driven tumors into a state of reductive stress, thereby exposing unique vulnerabilities and validating a novel therapeutic strategy. Here, the concept and mechanisms of reductive stress is reviewed, introduced methods for detecting it, and discussed its dual role in tumor progression and potential as a therapeutic target. Recent advances in nanomedicine, particularly in the design of functional nanomaterials, enabling precise modulation of cellular redox states are also highlighted. By selectively inducing reductive stress within tumors, nanomedicine offers a promising strategy to exploit tumor vulnerabilities, overcome drug resistance, and improve cancer therapy efficacy.
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Affiliation(s)
- Yumin Mao
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, P. R. China
| | - Xianping Liu
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, P. R. China
| | - Xu Chu
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, P. R. China
| | - Feixiang Chen
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, P. R. China
| | - Ruicheng Shi
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, P. R. China
| | - Zonghao Liu
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, P. R. China
| | - Yelin Wu
- Institute of Hepatobiliary and Pancreatic Surgery, Department of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, P. R. China
| | - Yanyan Liu
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, P. R. China
| | - Wenbo Bu
- Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, P. R. China
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12
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Kim SB, Lee JS, Jung CH, Cho EH, Seo HS, Lee GE, Kim HY, Lee SJ, Lee MJ, Oh HJY, Heo AJ, Han DH, Kwon YT, Ji CH. The Arg/N-degron pathway mediates the secretion of apoptotic exosomes under oxidative stress in cancer cell. iScience 2025; 28:112637. [PMID: 40520087 PMCID: PMC12167491 DOI: 10.1016/j.isci.2025.112637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 07/08/2024] [Accepted: 05/07/2025] [Indexed: 06/18/2025] Open
Abstract
Exosomes from cancer cells are versatile mediators of cell-to-cell communication, whose cargoes are dynamically loaded in response to various stress conditions. In this study, we demonstrate that under oxidative stress, cancer cells secrete exosomes that induce apoptosis in neighboring cells via the Arg/N-degron pathway. In this mechanism, Rab interacting lysosomal protein (RILP) is cleaved at Asp75 in response to oxidative stress which requires ATE1 R-transferase. The cleaved form of RILP recruits the ESCRT-II proteins VPS22 and VPS36 to endosomes from which the interluminal vesicles are invaginated generating exosomes. By using proteomics analyses, we also demonstrate that exosomes secreted from cancer cells upon oxidative stress are enriched apoptotic proteins including pro-apoptotic and anti-inflammatory cytokine ANXA1. These exosomes induce apoptosis of normal cancer cells transporting ANXA1 in an Arg/N-degron pathway-dependent manner. Our results show that the Arg/N-degron pathway modulates exosome-mediated apoptosis in cancer cells under oxidative stress underlying RILP-dependent secretion of ANXA1.
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Affiliation(s)
- Su Bin Kim
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
| | - Ji Su Lee
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
| | - Chan Hoon Jung
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
| | - Eun Hye Cho
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
| | - Ho Seok Seo
- Department of Transdisciplinary Medicine, Seoul National University Hospital, 71 Daehakro, Seoul, Republic of Korea
| | - Gee Eun Lee
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
| | - Hye Yeon Kim
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
| | - Su Jin Lee
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
| | - Min Ju Lee
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
| | - Hans Jin-young Oh
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ah Jung Heo
- Goethe University Frankfurt, Medical Faculty, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Do Hyun Han
- Department of Transdisciplinary Medicine, Seoul National University Hospital, 71 Daehakro, Seoul, Republic of Korea
| | - Yong Tae Kwon
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
- AUTOTAC Bio Inc., 225 Gasan digital 1-ro, Seoul, Republic of Korea
- Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080, Korea
- SNU Dementia Research Center, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
| | - Chang Hoon Ji
- Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
- AUTOTAC Bio Inc., 225 Gasan digital 1-ro, Seoul, Republic of Korea
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13
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Hu J, Yuan Z, Shu Y, Ren J, Yang J, Tang L, Wei X, Liu Y, Jin F, Xiao Q, Chen X, Wu N, Zhao W, Li Z, Zhang L. NRF2 maintains redox balance via ME1 and NRF2 inhibitor synergizes with venetoclax in NPM1-mutated acute myeloid leukemia. Cancer Metab 2025; 13:32. [PMID: 40533864 PMCID: PMC12177962 DOI: 10.1186/s40170-025-00401-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 06/12/2025] [Indexed: 06/22/2025] Open
Abstract
BACKGROUND Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations represents a distinct subtype of leukemia. Emerging evidence suggests that regulation of redox metabolism contributes to tumorigenesis and reveals a metabolic vulnerability in anti-tumor therapies. However, the role of redox homeostasis between reactive oxygen species (ROS) and antioxidant systems plays in NPM1-mutated AML has not been fully elucidated. METHODS First, ROS-related metabolic pathways in NPM1-mutated AML were analyzed using RNA-sequencing data. Intracellular and mitochondrial ROS levels in leukemia cells were detected using flow cytometry (FCM). The expression of nuclear factor (erythroid-derived 2)-like 2 (NRF2) was analyzed in public databases and further validated in AML primary blasts and cell lines by quantitative real-time PCR (qRT-PCR), western blotting, and immunofluorescence. Next, the mechanism underlying NRF2 expression was investigated through the RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP) and rescue experiments. Additionally, the downstream target gene of NRF2 was identified by bioinformatics analysis and chromatin immunoprecipitation (ChIP) assays. Furthermore, RNA interference and the NRF2 inhibitor ML385 were applied to explore the role of NRF2 in leukemia. Finally, the anti-leukemic effects of ML385 alone or in combination with the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax on AML cells were investigated using FCM analysis and western blotting, and further explored in cell line-derived xenograft (CDX) mouse models. RESULTS In this study, we identified significant ROS accumulation in leukemia cells with NPM1 mutations. Meanwhile, elevated NRF2 expression and its nuclear localization were observed in NPM1-mutated AML cells. The high NRF2 expression levels were at least partially induced by fat mass and obesity-associated protein (FTO) via m6A modification. Functionally, NRF2 exerts its antioxidant effects by transcriptionally upregulating malic enzyme 1 (ME1) expression and enhancing its activity. Targeting NRF2/ME1 axis reduced NADPH/NADP+ ratio, increased ROS levels, impaired leukemia cell viability, and promoted apoptosis. More importantly, NRF2 inhibitor ML385 in combination with venetoclax showed synergistic anti-leukemic activity in vitro and in vivo. CONCLUSION Overall, our findings provide new insight into the therapeutic potential of targeting NRF2 and guide the development of innovative combination therapies in NPM1-mutated AML.
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Affiliation(s)
- Jiayuan Hu
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Zihao Yuan
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Yan Shu
- Department of Laboratory Medicine, Chongqing University Fuling Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Jun Ren
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Jing Yang
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Lisha Tang
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Xingyu Wei
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Yongcan Liu
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Fangfang Jin
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Qiaoling Xiao
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Xinyi Chen
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Nan Wu
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Wen Zhao
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Ziwei Li
- Department of Laboratory Medicine, Chongqing University Fuling Hospital, School of Medicine, Chongqing University, Chongqing, China.
| | - Ling Zhang
- Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China.
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14
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Syahputra RA, Ahmed A, Asriadi, Barus AGB, Putri SK, Tan MW, Chandra QM, Brathennovic, Angiosaki Y, Lu FC, Clister D, Prananda AT, Halim P, Ribeiro RIMDA, Nurkolis F, Dalimunthe A. Ergothioneine as a Functional Nutraceutical: Mechanisms, Bioavailability, and Therapeutic Implications. J Nutr Biochem 2025:110006. [PMID: 40541582 DOI: 10.1016/j.jnutbio.2025.110006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 06/06/2025] [Accepted: 06/13/2025] [Indexed: 06/22/2025]
Abstract
Ergothioneine (EGT), a naturally occurring sulfur-containing antioxidant, has gained significant attention owing to its potent cytoprotective, anti-inflammatory, and neuroprotective properties. As a dietary-derived compound predominantly found in mushrooms, EGT exhibits remarkable stability and bioavailability, facilitated by a specific ergothioneine transporter that is highly expressed in mammalian tissues. Its ability to scavenge reactive oxygen and nitrogen species effectively mitigates oxidative stress, which is a key factor in the pathogenesis of various chronic diseases, including cardiovascular disorders, neurodegenerative conditions, and cancer. Emerging evidence has highlighted the role of EGT in modulating key signaling pathways involved in inflammation, apoptosis, and cellular homeostasis, suggesting its potential as a therapeutic agent. Clinical and preclinical studies have indicated its involvement in metabolic regulation, endothelial protection, and attenuation of neurodegeneration, further reinforcing its significance as a functional nutraceutical agent. This review provides a comprehensive analysis of EGT, including its biosynthesis, dietary sources, absorption mechanisms, and metabolism, and elucidates its therapeutic potential and mechanistic underpinnings for disease prevention and management. By summarizing recent advances in EGT research, this review aims to guide future investigations and support its broader application in clinical and nutritional sciences.
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Affiliation(s)
- Rony Abdi Syahputra
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia.
| | - Amer Ahmed
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125, Bari, Italy
| | - Asriadi
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Arnika Gloria Br Barus
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Sintia Karina Putri
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Michle William Tan
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Qhelen Mayline Chandra
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Brathennovic
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Yumiko Angiosaki
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Felice Chrismary Lu
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Davini Clister
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | - Arya Tjipta Prananda
- Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Princella Halim
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
| | | | - Fahrul Nurkolis
- Medical Research Center of Indonesia, Surabaya, Indonesia; State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta, 55281, Indonesia; Master of Basic Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Aminah Dalimunthe
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
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15
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Yang X, Yu L, Shao M, Yang H, Qi K, He G, Wang L, Kong D, Gu J, Xu X, Wang L. N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism. Cell Death Dis 2025; 16:458. [PMID: 40533443 PMCID: PMC12177039 DOI: 10.1038/s41419-025-07764-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 05/13/2025] [Accepted: 06/03/2025] [Indexed: 06/22/2025]
Abstract
As a predominant oncogenic driver in non-small cell lung cancer (NSCLC), EGFR frequently undergoes amplification or mutation, with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib constituting frontline therapy for advanced EGFR-mutant cases. However, both primary and acquired resistance significantly limit clinical efficacy. Here, we revealed that glutathione metabolic pathway controlled by glutathione peroxidase GPX2 was abnormally activated in gefitinib-resistant A549 and HCC827-GR cell lines. Mechanistically, GPX2 triggers Hedgehog signaling activation through releasing GLI transcriptional regulator, promoting cancer stem cell (CSC) characteristics and TKI resistance. Notably, N6-methyladenosine (m6A) modification on GPX2 mRNA mediated by METTL14 diminished its stability. In vivo, GPX2 deletion constrained glutathione metabolism and boosted the effectiveness of TKI in cell line-derived xenograft models. Collectively, these findings demonstrate that GPX2 serves as a positive regulator of both primary and acquired EGFR-TKI resistance and could be a promising therapeutic target for precise treatment of NSCLC.
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Affiliation(s)
- Xu Yang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Long Yu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Miaomiao Shao
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Huiling Yang
- Department of Pathology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Kangwei Qi
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Gaofei He
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Lanxin Wang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Di Kong
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Jianxin Gu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Xiaolin Xu
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
| | - Lan Wang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
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16
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Alonso-García S, Sánchez-Uceta P, Moreno-SanJuan S, Casado J, Puentes-Pardo JD, Khaldy H, Lopez-Pérez D, Zurita-Saavedra MS, González-Puga C, Carazo A, León J. Regulation of Stemness by NR1D2 in Colorectal Cancer. Biomedicines 2025; 13:1500. [PMID: 40564218 DOI: 10.3390/biomedicines13061500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2025] [Revised: 06/08/2025] [Accepted: 06/13/2025] [Indexed: 06/28/2025] Open
Abstract
Background: Nuclear Receptor Subfamily 1 Group D Member 2 (NR1D2), a transcription factor that regulates the circadian clock, has been described as an oncogene in colorectal cancer (CRC). In several types of cancer, NR1D2 regulates cancer progression and relapse through cancer stem cells (CSCs), although this aspect has not been studied in CRC. On the other hand, p53 is a tumour suppressor gene that appears mutated in approximately a 50% CRCs. Interestingly, p53 is considered to be a crucial nexus between circadian clock deregulation and cancer. In addition, p53 regulates CSC phenotypes. Methods: We developed an in vitro model in which NR1D2 was silenced in three isogenic cell lines with different p53 status. In addition, we analysed the expression of NR1D2 in a cohort of patients and determined its relationship with the characteristics of patients and tumours. Results: In the in vitro model, NRID2 silencing reduces cell growth and decreases stemness, although only in cells harbouring a wild type p53. In contrast, in cells lacking a functional p53 or harbouring a mutated one, NR1D2 knockout increases cell growth and stemness. In patients, NR1D2 expression correlates with poorly differentiated tumours and high expression of CSCs markers, although only in tumours with a wild type p53, corroborating the results obtained in the in vitro model. Conclusions: Although more research is needed to analyse the mechanism by which NR1D2 regulates stemness in a p53-dependent manner, our results highlight the possibility of using NR1D2 antagonists for treating this type of patient and to develop personalised medicine.
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Affiliation(s)
- Sandra Alonso-García
- Unidad de Gestión Clínica de Cirugía, Hospital Clínico Universitario San Cecilio, 18012 Granada, Spain
| | - Paula Sánchez-Uceta
- Instituto de Investigación Biosanitaria de Granada(ibs.GRANADA), 18012 Granada, Spain
| | - Sara Moreno-SanJuan
- Servicio de Microscopía y Citometría, Instituto de Investigación Biosanitaria de Granada(ibs.GRANADA), 18012 Granada, Spain
| | - Jorge Casado
- Instituto de Investigación Biosanitaria de Granada(ibs.GRANADA), 18012 Granada, Spain
| | - Jose D Puentes-Pardo
- Instituto de Investigación Biosanitaria de Granada(ibs.GRANADA), 18012 Granada, Spain
| | - Huda Khaldy
- Servicio de Biología Fundamental, Centro de Instrumentación Científica, Universidad de Granada, 18071 Granada, Spain
| | - David Lopez-Pérez
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - María Sol Zurita-Saavedra
- Unidad de Gestión Clínica de Cirugía, Hospital Clínico Universitario San Cecilio, 18012 Granada, Spain
| | - Cristina González-Puga
- Unidad de Gestión Clínica de Cirugía, Hospital Clínico Universitario San Cecilio, 18012 Granada, Spain
| | - Angel Carazo
- Instituto de Investigación Biosanitaria de Granada(ibs.GRANADA), 18012 Granada, Spain
- Unidad de Gestión Clínica de Microbiología, Hospital Universitario San Cecilio de Granada, 18016 Granada, Spain
| | - Josefa León
- Instituto de Investigación Biosanitaria de Granada(ibs.GRANADA), 18012 Granada, Spain
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Clínico Universitario San Cecilio, 18016 Granada, Spain
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17
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Gao L, Liao H, Chen Y, Ye C, Huang L, Xu M, Du J, Zhang J, Huang D, Cai S, Dong H. Airway microbiota associated D-phenylalanine promotes non-small cell lung cancer metastasis through epithelial mesenchymal transition. J Transl Med 2025; 23:673. [PMID: 40528221 DOI: 10.1186/s12967-025-06701-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 06/01/2025] [Indexed: 06/20/2025] Open
Abstract
BACKGROUND Lung cancer is the leading cause of cancer-related death worldwide, and patients with distant metastasis have a poor prognosis. Various studies have reported that microbiota and metabolites significantly differ between healthy individuals and lung cancer patients. However, the effects of metabolites on tumor formation and metastasis are unclear. Therefore, our study aimed to determine the correlation between airway metabolites and microbiota, along with their respective roles in lung cancer metastasis. METHODS Bronchoalveolar lavage fluid (BALF) samples were collected from 30 non-small cell lung cancer (NSCLC) patients, including 11 patients without metastasis (M0) and 19 patients with metastasis (M1). Integrated pathogenic metagenomic and Liquid chromatography-mass spectrometry (LC‒MS) analyses were employed to explore differences between two groups. The omics data were analyzed and integrated via Spearman's correlation coefficient. Specific metabolites were subsequently used to intervene in lung cancer cells and animal models to assess their influence on tumor metastasis. RESULTS A total of 801 metabolites were identified in the BALF of all patients. Compared with those in the M0 group, 48 metabolites in the M1 group were significantly different. D-phenylalanine was notably upregulated in M1 and was positively related to Metamycoplasma salivarium. Intranasal administration of D-phenylalanine promoted tumor intrapulmonary metastasis and induced epithelial mesenchymal transition (EMT) process in NSCLC mouse models. Moreover, D-phenylalanine promotes the proliferation of non-small cell lung cancer cells and facilitates their migration and invasion via EMT. CONCLUSION The airway microbiota associated D-phenylalanine could promote lung cancer metastasis via EMT, which could be a new predictor for the diagnosis of tumor metastasis in NSCLC patients.
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Affiliation(s)
- Lin Gao
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China
| | - Hua Liao
- The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Yuehua Chen
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Cuiping Ye
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Liping Huang
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, 350001, China
- Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001, China
- Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian Province, 350001, China
| | - Mingming Xu
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiangzhou Du
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinming Zhang
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Danhui Huang
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shaoxi Cai
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Hangming Dong
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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18
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Xia F, Sha Y, Jin Y, Yang J, Chen C, Gong B, Liu Y, Zhao Q. Autophagy inhibition amplifies anti-tumor immunity effect of dinutuximab beta on neuroblastoma via the VEGFR/AKT/mTOR and ROS/NF-κB pathways. Int Immunopharmacol 2025; 158:114862. [PMID: 40378433 DOI: 10.1016/j.intimp.2025.114862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 05/08/2025] [Accepted: 05/09/2025] [Indexed: 05/18/2025]
Abstract
Dinutuximab beta has shown limited efficacy in treating high-risk neuroblastoma (NB). Combining autophagy inhibitors with immune checkpoint inhibitors (ICIs) has proven effective in many malignancies. However, the anti-tumor effects of autophagy inhibition in conjunction with anti-GD2 immunotherapy remain unknown. In this study, dinutuximab beta induces anti-proliferation and anti-EMT activity in NB cells. Dinutuximab beta also triggers autophagy in NB cells, and inhibition of the VEGFR pathway with anlotinib amplifies dinutuximab beta-induced autophagy. In addition, dinutuximab beta induces the synthesis of the chemokine CXCL9 and the infiltration of CD8+ T cells. Mechanistically, dinutuximab beta inhibits the VEGFR/AKT/mTOR and ROS/NF-κB pathways. Furthermore, autophagy inhibition by CQ enhances CXCL9 expression and anti-tumor T cell responses of single anti-GD2 therapy in vitro and in vivo. Collectively, this study suggests autophagy inhibitors may be a promising strategy for enhancing therapeutic efficacy in NB in conjunction with anti-GD2 immunotherapy.
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Affiliation(s)
- Fantong Xia
- Radiation Oncology Center, Chongqing University Cancer Hospital, College of Medicine, Chongqing University, Chongqing, China
| | - Yongliang Sha
- Department of General Surgery, Xuzhou Central Hospital, Xuzhou, China
| | - Yan Jin
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jiaxing Yang
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Chong Chen
- Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Baocheng Gong
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yun Liu
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Qiang Zhao
- Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
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19
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Ma J, Qiu J, Wang S. Tumor Microenvironment-responsive Nanocatalyst for Targeted Chemodynamic Cancer Therapy. Adv Healthc Mater 2025:e2501746. [PMID: 40525679 DOI: 10.1002/adhm.202501746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Revised: 05/26/2025] [Indexed: 06/19/2025]
Abstract
To address the challenges of insufficient hydrogen peroxide (H2O2) levels, rapid Fe3+ precipitation, and a slow Fenton reaction cycle, tumor-activated, self-accelerating CDT nanocatalysts are synthesized, comprising poly (lactic-co-glycolic acid) (PLGA)-encapsulated Ca-Fe peroxide clusters and polyarginine (R). Nanocatalysts are camouflaged with cancer cell membranes (CCM) to enhance tumor targeting. Additionally, polyarginine tailored the PLGA responsiveness to low H2O2 levels (50-100 µm). H2O2 triggered the degradation of PLGA, releasing CaFe clusters to produce Fe3+/Fe2+ and additional H2O2, sustaining the Fenton reaction. Simultaneously, polyarginine releases nitric oxide (NO) in the presence of H2O2, facilitating Fe3+ reduction to Fe2+ and amplifying •OH generation. In vitro cellular studies demonstrate significantly improved homotypic tumor targeting (6.5-fold increase) and deep spheroid penetration (>120 µm), resulting in improved tumor permeability and elevated •OH generation. Additionally, the nanoparticles exhibit dose-dependent cytotoxicity, and polyarginine notably enhanced the cytotoxicity of CCM-PLGA-CaFe NPs, reducing the IC50 value from 216.9 to 43.38 µg mL-1. Apoptosis/necrosis assay reveals that the elevated •OH generation by CCM-PLGA-CaFe-R NPs preferentially induced necrosis, effectively inhibiting tumor cell proliferation by 76.3% ± 8.4% over a 7-day treatment. Consequently, this TME-responsive, self-accelerating CDT platform demonstrates enhanced therapeutic efficacy through improved tumor targeting, sustained Fenton reaction, and amplified radical generation.
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Affiliation(s)
- Jun Ma
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Jingjing Qiu
- Department of Mechanical Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Shiren Wang
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
- Department of Industrial Systems and Engineering, Texas A&M University, College Station, TX, 77843, USA
- Department of Materials Science and Engineering, Texas A&M University, College Station, TX, 77843, USA
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20
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Znaidi R, Massiani-Beaudoin O, Mailly P, Monnet H, Bonnifet T, Joshi RL, Fuchs J. Nuclear translocation of the LINE-1 encoded ORF1 protein alters nuclear envelope integrity in human neurons. Brain Res 2025; 1857:149579. [PMID: 40157412 DOI: 10.1016/j.brainres.2025.149579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Accepted: 03/17/2025] [Indexed: 04/01/2025]
Abstract
LINE-1 retrotransposons are increasingly implicated in aging and neurodegenerative diseases, yet the precise pathogenic mechanisms remain elusive. While the endonuclease and reverse transcriptase activities of LINE-1-encoded ORF2p can induce DNA damage and inflammation, a role of LINE-1 ORF1p in cellular dysfunctions stays unassigned. Here we demonstrate, using a neuronal cellular model, that ORF1p translocates into the nucleus upon arsenite-induced stress, directly interacting with nuclear import (KPNB1), nuclear pore complex (NUP153), and nuclear lamina (Lamin B1) proteins. Nuclear translocation of ORF1p disrupts nuclear integrity, nucleocytoplasmic transport, and heterochromatin structure, features linked to neurodegeneration and aging. Elevated nuclear ORF1p levels induced either by arsenite-induced stress, ORF1p overexpression, or as observed in Parkinson's disease post-mortem brain tissues correlate with impaired nuclear envelope (NE) morphology. Stress-induced nuclear alterations are mitigated by blocking ORF1p nuclear import or with the anti-aging drug remodelin. This study thus reveals a pathogenic action of nuclear ORF1p in human neurons driving NE alterations and thereby contributing to LINE-1-mediated cell toxicity.
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Affiliation(s)
- Rania Znaidi
- CIRB, Collège de France, Université PSL, CNRS, INSERM, 75005 Paris, France
| | | | - Philippe Mailly
- Orion Imaging Facility, CIRB, Collège de France, Université PSL, CNRS, INSERM, Labex Memolife, 75005 Paris, France
| | - Héloïse Monnet
- Orion Imaging Facility, CIRB, Collège de France, Université PSL, CNRS, INSERM, Labex Memolife, 75005 Paris, France
| | - Tom Bonnifet
- CIRB, Collège de France, Université PSL, CNRS, INSERM, 75005 Paris, France
| | - Rajiv L Joshi
- CIRB, Collège de France, Université PSL, CNRS, INSERM, 75005 Paris, France.
| | - Julia Fuchs
- CIRB, Collège de France, Université PSL, CNRS, INSERM, 75005 Paris, France.
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21
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Wang M, Xiao Y, Miao J, Zhang X, Liu M, Zhu L, Liu H, Shen X, Wang J, Xie B, Wang D. Oxidative Stress and Inflammation: Drivers of Tumorigenesis and Therapeutic Opportunities. Antioxidants (Basel) 2025; 14:735. [PMID: 40563367 DOI: 10.3390/antiox14060735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2025] [Revised: 06/08/2025] [Accepted: 06/12/2025] [Indexed: 06/28/2025] Open
Abstract
As two pivotal regulatory factors in cancer biology, oxidative stress and inflammation interact dynamically through complex network mechanisms to influence tumor initiation, progression, and treatment resistance. Oxidative stress induces genomic instability, oncogenic signaling activation, and tumor microenvironment (TME) remodeling via the abnormal accumulation of reactive oxygen species (ROS) or reactive nitrogen species (RNS). Conversely, inflammation sustains malignant phenotypes by releasing pro-inflammatory cytokines and chemokines and promoting immune cell infiltration. These processes create a vicious cycle via positive feedback loops whereby oxidative stress initiates inflammatory signaling, while the inflammatory milieu further amplifies ROS/RNS production, collectively promoting proliferation, migration, angiogenesis, drug resistance, and immune evasion in tumor cells. Moreover, their crosstalk modulates DNA damage repair, metabolic reprogramming, and drug efflux pump activity, significantly impacting the sensitivity of cancer cells to chemotherapy, radiotherapy, and targeted therapies. This review systematically discusses these advances and the molecular mechanisms underlying the interplay between oxidative stress and inflammation in cancer biology. It also explores their potential as diagnostic biomarkers and prognostic indicators and highlights novel therapeutic strategies targeting the oxidative stress-inflammation axis. The goal is to provide a theoretical framework and translational roadmap for developing synergistic anti-tumor therapies.
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Affiliation(s)
- Meimei Wang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Yaping Xiao
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Jie Miao
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Xin Zhang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Meng Liu
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Longchao Zhu
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Hongxin Liu
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Xiaoyan Shen
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Jihui Wang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
| | - Biao Xie
- Department of Gastroenterology, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510440, China
| | - Di Wang
- School of Life and Health Technology, Dongguan University of Technology, Dongguan 523808, China
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22
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Alves R, Ventura F, Jorge J, Marques G, Coucelo M, Diamond J, Oliveiros B, Pereira A, Freitas-Tavares P, Almeida AM, Gonçalves AC, Sarmento-Ribeiro AB. Genetic Variants in Oxidative Stress-Related Genes and Their Impact on Prognosis and Treatment Response in Chronic Myeloid Leukemia Patients. Int J Mol Sci 2025; 26:5682. [PMID: 40565143 DOI: 10.3390/ijms26125682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2025] [Revised: 05/18/2025] [Accepted: 06/11/2025] [Indexed: 06/28/2025] Open
Abstract
Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the BCR::ABL1 fusion gene, which codifies the BCR-ABL protein with increased tyrosine kinase activity. Despite the clinical results for the outstanding tyrosine kinase inhibitors (TKIs), drug resistance is a problem in CML management. Genetic variants that alter redox homeostasis by changing antioxidant enzyme expression or activity may influence patient responses and could enhance patient stratification. We aimed to assess the association of SOD2, CAT GPX1, NRF2, and KEAP1 genetic variants with TKI response and disease prognosis. For this purpose, we genotyped the variants rs4880 (SOD2), rs1050450 (GPX1), rs1001179 (CAT), rs6721961, rs4893819, rs35652124, rs6706649, rs13001694 (NFE2L2), and rs113540846 (KEAP1) via PCR in 187 CML patients. Our results show that variants in genes related to oxidative stress influence the development and degree of TKI resistance (allele G and GG genotypes of GPX1 and CT genotype of NFE2L2 rs4893819), the appearance of mutations in the BCR::ABL1 gene (AG genotype of NFE2L2 rs13001694 and genetic profile GGCTTCCCGG of the NFE2L2/KEAP1 axis), disease evolution (AG genotype of SOD2 and CT genotype of NFE2L2 rs4893819), and overall survival (CC genotype of CAT and GG genotype of NFE2L2 rs13001694) of CML patients. Our study found that variants in oxidative stress-related genes impact treatment response and outcomes in CML.
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MESH Headings
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Oxidative Stress/genetics
- Female
- Male
- Middle Aged
- Prognosis
- NF-E2-Related Factor 2/genetics
- Adult
- Aged
- Glutathione Peroxidase GPX1
- Polymorphism, Single Nucleotide
- Kelch-Like ECH-Associated Protein 1/genetics
- Drug Resistance, Neoplasm/genetics
- Protein Kinase Inhibitors/therapeutic use
- Superoxide Dismutase/genetics
- Glutathione Peroxidase/genetics
- Genotype
- Young Adult
- Aged, 80 and over
- Fusion Proteins, bcr-abl/genetics
- Catalase/genetics
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Affiliation(s)
- Raquel Alves
- Laboratory of Oncobiology and Hematology (LOH) and University Clinics of Hematology and Oncology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR)-Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal
| | - Filipa Ventura
- Laboratory of Oncobiology and Hematology (LOH) and University Clinics of Hematology and Oncology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Joana Jorge
- Laboratory of Oncobiology and Hematology (LOH) and University Clinics of Hematology and Oncology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR)-Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal
| | - Gilberto Marques
- Clinical Pathology Service, Centro Hospitalar Universitário de Coimbra (CHUC), 3000-061 Coimbra, Portugal
| | - Margarida Coucelo
- Coimbra Institute for Clinical and Biomedical Research (iCBR)-Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Hematology Service, Centro Hospitalar Universitário de Coimbra (CHUC), 3000-061 Coimbra, Portugal
| | - Joana Diamond
- Hemato-Oncology Laboratory, Instituto Português de Oncologia de Lisboa Francisco Gentil EPE, 1099-023 Lisbon, Portugal
| | - Bárbara Oliveiros
- Coimbra Institute for Clinical and Biomedical Research (iCBR)-Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Amélia Pereira
- Coimbra Institute for Clinical and Biomedical Research (iCBR)-Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Medicine Service, Hospital da Luz, 3020-479 Coimbra, Portugal
- Medicine Department, Hospital Distrital da Figueira da Foz, EPE, 3094-001 Figueira da Foz, Portugal
| | - Paulo Freitas-Tavares
- Orthopedic Oncology Department, Centro Hospitalar Universitário de Coimbra (CHUC), 3000-061 Coimbra, Portugal
| | - António M Almeida
- Hospital da Luz Lisboa, 1500-650 Lisbon, Portugal
- Centro de Investigação Interdisciplinar em Saúde (CIIS), Faculdade de Medicina, Universidade Católica Portuguesa de Lisboa, 2635-631 Lisbon, Portugal
| | - Ana Cristina Gonçalves
- Laboratory of Oncobiology and Hematology (LOH) and University Clinics of Hematology and Oncology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR)-Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal
| | - Ana Bela Sarmento-Ribeiro
- Laboratory of Oncobiology and Hematology (LOH) and University Clinics of Hematology and Oncology, Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR)-Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine University of Coimbra (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal
- Hematology Service, Centro Hospitalar Universitário de Coimbra (CHUC), 3000-061 Coimbra, Portugal
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23
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Geaneotes PJ, Floreancig PE. Strategy-Level Prodrug Synthesis. Chemistry 2025; 31:e202501115. [PMID: 40317559 PMCID: PMC12160975 DOI: 10.1002/chem.202501115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/30/2025] [Accepted: 05/02/2025] [Indexed: 05/07/2025]
Abstract
Organic synthesis uniquely provides opportunities to access molecules that serve defined purposes. Medicinal chemistry illustrates this attribute well with prodrug design, whereby a drug undergoes a late-stage conversion to a conditionally responsive active medicinal agent (AMA), being a notable example. Prodrugs are becoming increasingly important in medicinal chemistry but common approaches to introduce biologically responsive groups are limited in the chemoselectivity and scope of available functionalization reactions. This Concept article describes strategy-level prodrug synthesis, which is a powerful extension of classical prodrug formation that initiates sequences with the objective of introducing functionality early in a sequence to achieve greater scope, site-selectivity, and chemoselectivity for the incorporation of the biologically responsive group. Examples of functionalization using alkyne hydroamination, Curtius reaction, and alkene metathesis are highlighted along with the use of the prodrugs for biological applications.
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Affiliation(s)
- Paul J. Geaneotes
- Department of ChemistryUniversity of PittsburghPittsburghPennsylvania15260USA
| | - Paul E. Floreancig
- Department of ChemistryUniversity of PittsburghPittsburghPennsylvania15260USA
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24
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Chen C, Carrillo ND, Chen M, Wen T, Awasthi P, Anderson RA, Cryns VL. Regulation of NRF2 by Stably associated Phosphoinositides and Small Heat Shock Proteins in Response to Stress. J Biol Chem 2025:110367. [PMID: 40516875 DOI: 10.1016/j.jbc.2025.110367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2025] [Revised: 06/02/2025] [Accepted: 06/09/2025] [Indexed: 06/16/2025] Open
Abstract
Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the stability and function of NRF2 is regulated by the type I phosphatidylinositol phosphate kinase γ (PIPKIγ), which binds NRF2 and is required to stably couple phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to NRF2 in response to oxidative stress. Stress also induces the interaction of the small heat shock protein HSP27 and NRF2 and this interaction is enhanced by PtdIns(4,5)P2. Silencing PIPKIγ or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, and sensitizes cells to oxidative stress. These data demonstrate an unexpected collaboration between phosphoinositides, which are stably coupled to NRF2, and HSP27, which is recruited to NRF2 by a phosphoinositide-dependent mechanism to regulate NRF2 stability and function. These findings also point to PIPKIγ and HSP27 as drug targets to destabilize NRF2 in cancer.
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Affiliation(s)
- Changliang Chen
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA; Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Noah D Carrillo
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA; Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Mo Chen
- Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Tianmu Wen
- Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Poorwa Awasthi
- Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Richard A Anderson
- Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA.
| | - Vincent L Cryns
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA; Carbone Cancer Center, University of Wisconsin-Madison, School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA.
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25
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Deng Q, Hua A, Zhao Q, Zhang Z, Yang T, Wang Q, Yang X, Li Z. Modulating tumor acidity with hydroxyethyl starch-based nanoparticles by targeting CA9 to eliminate cancer stem cells and overcome immunosuppression. Biomaterials 2025; 324:123501. [PMID: 40527086 DOI: 10.1016/j.biomaterials.2025.123501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 05/27/2025] [Accepted: 06/12/2025] [Indexed: 06/19/2025]
Abstract
The acidic microenvironment in solid tumors, primarily driven by Warburg effect, promotes tumor progression, immune evasion, and resistance to therapy. Cancer stem cells (CSCs), a critical subset within tumor tissues, exacerbate this acidity through overexpression of pH-regulating proteins such as carbonic anhydrase IX (CA9), which plays a pivotal role in maintaining pH homeostasis, contributes to immune suppression, and sustains CSC stemness and proliferation. In this study, we designed CA9 inhibitor (CAi) coupled hydroxyethyl starch-based nanoparticles (CHHD-Cu NPs) that integrate doxorubicin (DOX) mediated chemotherapy with copper ions (Cu2+) mediated chemodynamic therapy to target and eliminate CA9-expressing CSCs. Upon administration, CHHD-Cu NPs bind to CA9 and disrupt pH regulation, thereby lowering intracellular pH and raising extracellular pH. This pH modulation enhances intracellular releases of DOX and Cu2+ and alleviates extracellular acidity to boost effector T cells infiltration and activity. Our rationally designed CHHD-Cu NPs eliminate CSCs in two ways: firstly, by robust intracellular DOX- and copper-induced cytotoxicity, and secondly, via pH modulation-mediated activation of anti-tumor immunity. Our strategy offers novel approaches for treatment of immunosuppressive solid tumors.
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Affiliation(s)
- Qingyuan Deng
- Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Ao Hua
- Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Qingfu Zhao
- Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Zhijie Zhang
- Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Tian Yang
- Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Qiang Wang
- Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Xiangliang Yang
- Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, PR China.
| | - Zifu Li
- Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, PR China.
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26
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Rapozzi V, Comuzzi C, Di Giorgio E, Xodo LE. KRAS and NRF2 drive metabolic reprogramming in pancreatic cancer cells: the influence of oxidative and nitrosatice stress. Front Cell Dev Biol 2025; 13:1547582. [PMID: 40567499 PMCID: PMC12187747 DOI: 10.3389/fcell.2025.1547582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 05/26/2025] [Indexed: 06/28/2025] Open
Abstract
Cancer cells are subject to metabolic reprogramming, which leads to a sustained production of reactive oxygen species (ROS). Increased oxidative stress contributes to genomic instability and promotes malignant transformation. To counteract excessive ROS levels, cells activate nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of redox homeostasis that coordinates the transcription of a wide range of antioxidant and cytoprotective genes. This review examines the metabolic adaptations controlled by the KRAS-NRF2 axis under oxidative stress conditions. In addition, we highlight a novel function of NRF2 in regulating the expression of NOS2 by binding to a DNA enhancer element, thereby modulating the production of reactive nitrogen species (RNS). Finally, we discuss novel molecular strategies aimed at disrupting adaptive antioxidant responses in cancer cells and provide insights into combinatorial therapeutic approaches targeting redox balance in cancer.
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Affiliation(s)
- Valentina Rapozzi
- Department of Medicine, Laboratory of Biochemistry, University of Udine, Udine, Italy
| | - Clara Comuzzi
- Department of Agricultural Food Environmental and Animal Science, University of Udine, Udine, Italy
| | - Eros Di Giorgio
- Department of Medicine, Laboratory of Biochemistry, University of Udine, Udine, Italy
| | - Luigi E. Xodo
- Department of Medicine, Laboratory of Biochemistry, University of Udine, Udine, Italy
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27
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Huang Q, Jing Y, Xiong L, Li L, Feng J, Cheng J. The interplay between driver mutation and oxidative stress in colorectal cancer: from pathogenesis to therapeutics. J Transl Med 2025; 23:635. [PMID: 40490762 DOI: 10.1186/s12967-025-06640-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Accepted: 05/23/2025] [Indexed: 06/11/2025] Open
Abstract
Colorectal cancer (CRC) is a multifaceted disease influenced by genetic mutations and environmental factors, especially oxidative stress. Driver mutations are pivotal in CRC initiation and progression and alter key signaling pathways involved in cell proliferation, apoptosis, and genomic stability. Concurrently, oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, plays a crucial role in CRC development by promoting DNA damage, lipid peroxidation, and redox signaling dysregulation. The molecular mechanisms linking driver mutations and oxidative stress pathways underscore their collective or antagonistic impact on CRC heterogeneity, therapeutic responses, and clinical outcomes. Insights into mutation-specific vulnerabilities and redox modulation offer promising avenues for targeted therapies and personalized medicine approaches in CRC treatment. Here, we discuss the intricate interplay between driver mutations and oxidative stress, highlight emerging trends, and propose future research directions to advance our understanding of CRC pathogenesis and optimize therapeutic interventions.
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Affiliation(s)
- Qi Huang
- Department of Anorectal Surgery, The People's Hospital of Leshan, Leshan, 614000, China
| | - Yuan Jing
- Department of Medical Records, The People's Hospital of Leshan, Leshan, 614000, China
| | - Lihua Xiong
- Department of Dermatology, Cheng Du Xinjin District Hospital of Traditional Chinese Medicine, Chengdu, 610500, China
| | - Lei Li
- Department of Anorectal Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Jingjuan Feng
- Department of Traditional Chinese Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Jian Cheng
- Department of Traditional Chinese Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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28
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Tamir TY, Chaudhary S, Li AX, Trojan SE, Flower CT, Vo P, Cui Y, Davis JC, Mukkamala R, Venditti FN, Hillis AL, Toker A, Vander Heiden MG, Spinelli JB, Kennedy NJ, Davis RJ, White FM. Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity. Mol Cell 2025; 85:2211-2229.e8. [PMID: 40441152 PMCID: PMC12147527 DOI: 10.1016/j.molcel.2025.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 02/24/2025] [Accepted: 05/05/2025] [Indexed: 06/11/2025]
Abstract
Coordination of adaptive metabolism through signaling networks is essential for cellular bioenergetics and homeostasis. Phosphorylation of metabolic enzymes provides a rapid, efficient, and dynamic mechanism to regulate metabolic networks. Our structural analysis stratified phosphosites on metabolic enzymes based on proximity to functional and dimerization domains. Most phosphosites occur on oxidoreductases and are enriched near substrate, cofactor, active sites, or dimer interfaces. Despite low stoichiometry, phosphotyrosine (pY) is overrepresented in functional domains. Using high-fat diet (HFD)-induced obesity in C57BL/6J mice and multiomics, we measured HFD-induced sex-specific dysregulation of pY and metabolites, which was reversible with the antioxidant butylated hydroxyanisole (BHA). Computational modeling revealed predictive pY sites for HFD- or BHA-induced metabolite changes. We characterized functional roles for predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPR interference (CRISPRi) rescue and stable isotope tracing. Our findings reveal mechanisms whereby cellular signaling fine-tunes enzyme activity and metabolism.
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Affiliation(s)
- Tigist Y Tamir
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
| | - Shreya Chaudhary
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Annie X Li
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Sonia E Trojan
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Faculty of Medicine, Chair of Medical Biochemistry, Jagiellonian University Medical College, Krakow, Poland
| | - Cameron T Flower
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA; Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Paula Vo
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Yufei Cui
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Jeffrey C Davis
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Rachit Mukkamala
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Francesca N Venditti
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Alissandra L Hillis
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Alex Toker
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Matthew G Vander Heiden
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jessica B Spinelli
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Norman J Kennedy
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Roger J Davis
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Forest M White
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
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29
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Xu Q, Liu P, Nie Q, Chu Y, Yao X, Fang J, Zhang J. Structural simplification of quaternary benzophenanthridine alkaloids generating a candidate for the treatment of non-small cell lung cancer. Eur J Med Chem 2025; 290:117551. [PMID: 40147342 DOI: 10.1016/j.ejmech.2025.117551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
Quaternary benzophenanthridine alkaloids (QBAs), such as sanguinarine, chelerythrine, and nitidine, possess diverse pharmacological activities. This study presents a simplified structure for QBAs, yielding twelve three-membered phenanthridine alkaloids. Notably, compound 6f demonstrates enhanced potency in selectively inhibiting thioredoxin reductase (TrxR, TXNRD) and exhibits significant cytotoxicity against non-small cell lung cancer (NSCLC) cells. While TrxR is a selenoenzyme, many of its inhibitors react with biological thiols; however, 6f shows minimal reactivity with thiols such as glutathione (GSH) and cysteine. Mechanistic investigations reveal that 6f stimulates reactive oxygen species production, reduces intracellular thiols, and decreases the GSH/GSSG ratio, leading to cell apoptosis through oxidative stress. Moreover, significant tumor regression has been observed in nude mice with NSCLC following treatment with 6f. The pronounced anticancer activity and possible mechanism of action of 6f suggest its potential as a candidate for further development in NSCLC therapy.
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MESH Headings
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/metabolism
- Benzophenanthridines/chemistry
- Benzophenanthridines/pharmacology
- Benzophenanthridines/chemical synthesis
- Benzophenanthridines/therapeutic use
- Humans
- Lung Neoplasms/drug therapy
- Lung Neoplasms/pathology
- Lung Neoplasms/metabolism
- Animals
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/therapeutic use
- Structure-Activity Relationship
- Mice
- Drug Screening Assays, Antitumor
- Molecular Structure
- Alkaloids/chemistry
- Alkaloids/pharmacology
- Alkaloids/chemical synthesis
- Cell Proliferation/drug effects
- Mice, Nude
- Thioredoxin-Disulfide Reductase/antagonists & inhibitors
- Thioredoxin-Disulfide Reductase/metabolism
- Apoptosis/drug effects
- Dose-Response Relationship, Drug
- Cell Line, Tumor
- Enzyme Inhibitors/pharmacology
- Enzyme Inhibitors/chemistry
- Enzyme Inhibitors/chemical synthesis
- Reactive Oxygen Species/metabolism
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/pathology
- Neoplasms, Experimental/metabolism
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Affiliation(s)
- Qianhe Xu
- School of Pharmacy, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, China
| | - Pei Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, 999078, China
| | - Qiuying Nie
- School of Pharmacy, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, China
| | - Yajun Chu
- School of Pharmacy, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, China
| | - Xiaojun Yao
- Faculty of Applied Sciences, Macao Polytechnic University, Macao, 999078, China
| | - Jianguo Fang
- School of Pharmacy, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, China; School of Chemistry and Chemical Engineering, Nanjing University of Science & Technology, Nanjing, 210094, China.
| | - Junmin Zhang
- School of Pharmacy, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, 999078, China.
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30
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Kafeel S, Palmiero G, Salzillo A, Ragone A, Naviglio S, Sapio L. Unravelling the Adiponectin Hallmark and Exploring the Therapeutic Potential of Its Receptor Agonists in Cancer Metabolic Reprogramming. Biomolecules 2025; 15:820. [PMID: 40563460 DOI: 10.3390/biom15060820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2025] [Revised: 05/29/2025] [Accepted: 06/01/2025] [Indexed: 06/28/2025] Open
Abstract
As the most abundant fat-derived hormone, adiponectin plays an essential role in regulating energy homeostasis. Current evidence proposes the serum levels of adiponectin as a risk factor and a diagnostic/prognostic biomarker in cancer. Moreover, distinctive antineoplastic features have also been reported as a result of adiponectin supplementation in preclinical models. Mapping of the cancer-associated metabolic changes has elucidated a highly adaptable and interconnected system that allows malignant cells to sustain their growth and survival. Along with the pyruvate into acetyl-CoA conversion, downregulation of both lactate dehydrogenase and glycolysis-related genes depicts the main adiponectin-induced perturbations affecting glucose metabolism in cancer. Meanwhile, a multi-level approach involving lipid trafficking, catabolism, and de novo synthesis has been attributed to adiponectin in malignancies. The adiponectin receptor agonist AdipoRon has recently been recognized as a promising antineoplastic compound. Remarkably, AdipoRon-mediated changes in cancer metabolism occur together with its antiproliferative potential. This review aimed at recapitulating the modulatory effects of adiponectin, as well as those of its synthetic receptor agonists, in driving metabolic alterations in cancerous cells. A critical discussion is also conducted to deduce whether the adiponectin axis could serve as a putative target to address the metabolic reprogramming in cancer progression.
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Affiliation(s)
- Sanober Kafeel
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Giuseppina Palmiero
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Alessia Salzillo
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Angela Ragone
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
- Department of Mechanistic Cell Biology, Max Plank Institute of Molecular Physiology, 44227 Dortmund, Germany
| | - Silvio Naviglio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Luigi Sapio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
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31
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Sun Y, He J, Chen W, Wang Y, Wang K, Zhou M, Zheng Y. Inhalable DNase I@Au hybrid nanoparticles for radiation sensitization and metastasis inhibition by elimination of neutrophil extracellular traps. Biomaterials 2025; 317:123095. [PMID: 39813970 DOI: 10.1016/j.biomaterials.2025.123095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 01/18/2025]
Abstract
High-dose radiation therapy is a widely used clinical strategy to inhibit tumor growth. However, the rapid generation of excessive reactive oxygen species (ROS) triggers the formation of neutrophil extracellular traps (NETs), which capture free tumor cells in the bloodstream, promoting metastasis. In this study, we developed a hybrid nanoparticle composed of DNase I and gold (DNase I@Au) to enhance radiotherapy efficacy while mitigating metastasis by precisely eliminating NETs. The DNase I@Au nanoparticles, administered via aerosol inhalation, are efficiently delivered to lung tumor tissue, improving radiosensitization and reducing tumor size. Crucially, the nanoparticles could gradually release DNase I, effectively degrading ROS-induced NETs and preventing the interaction of free malignant cells with tumor sites or vasculature, thereby inhibiting metastasis. Therefore, we provide an enzyme and sensitizer co-loaded strategy that offers a promising approach to improve the therapeutic outcome of radiotherapy and reduce the risk of lung cancer metastasis under ROS stimulation.
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Affiliation(s)
- Yuchao Sun
- Department of Urology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Jian He
- University-University of Edinburgh Institute (ZJU-UoE Institute), and liangzhu Laboratory, Zhejiang University School of Medicine, Zhejiang University, Haining, 314400, China; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Weiyu Chen
- Department of Respiratory and Critical Care Medicine, Center for Oncology Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China; Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer, Yiwu, 322000, China
| | - Yongfang Wang
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kai Wang
- Department of Respiratory and Critical Care Medicine, Center for Oncology Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China; Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer, Yiwu, 322000, China
| | - Min Zhou
- Department of Urology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China; University-University of Edinburgh Institute (ZJU-UoE Institute), and liangzhu Laboratory, Zhejiang University School of Medicine, Zhejiang University, Haining, 314400, China; Key Laboratory of Cancer Prevention and Intervention of China (MOE), Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Yichun Zheng
- Department of Urology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
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32
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Zhao C, Wang H, Xu C, Fang F, Gao L, Zhai N, Zhong Y, Wang X. The critical role of the Hippo signaling pathway in renal fibrosis. Cell Signal 2025; 130:111661. [PMID: 39988289 DOI: 10.1016/j.cellsig.2025.111661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 02/25/2025]
Abstract
Renal fibrosis is a fundamental pathological change in the progression of various chronic kidney diseases to the end stage of renal disease. The Hippo signaling pathway is an evolutionary highly conserved signaling pathway that is involved in the regulation of organ size, tissue regeneration, and human reproduction and development. Currently, many studies have shown that it is closely associated with renal diseases, such as, renal fibrosis, diabetic nephropathy, and renal cancer. Here, we review the current researches on the effect of Hippo signaling pathway on renal fibrosis, which provides new ideas and theoretical basis for clinical therapeutics of renal fibrosis.
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Affiliation(s)
- Chenchen Zhao
- Hebei Key Laboratory of Liver and Kidney Diseases of Integrated Traditional Chinese and Western Medicine 7th Floor, Scientific Research Building, Hebei University of Traditional Chinese Medicine, Shijiazhuang City, China
| | - Hongshuang Wang
- Hebei Key Laboratory of Liver and Kidney Diseases of Integrated Traditional Chinese and Western Medicine 7th Floor, Scientific Research Building, Hebei University of Traditional Chinese Medicine, Shijiazhuang City, China
| | - Chang Xu
- Hebei Key Laboratory of Liver and Kidney Diseases of Integrated Traditional Chinese and Western Medicine 7th Floor, Scientific Research Building, Hebei University of Traditional Chinese Medicine, Shijiazhuang City, China
| | - Fang Fang
- Hebei Key Laboratory of Liver and Kidney Diseases of Integrated Traditional Chinese and Western Medicine 7th Floor, Scientific Research Building, Hebei University of Traditional Chinese Medicine, Shijiazhuang City, China
| | - Lanjun Gao
- Hebei Key Laboratory of Liver and Kidney Diseases of Integrated Traditional Chinese and Western Medicine 7th Floor, Scientific Research Building, Hebei University of Traditional Chinese Medicine, Shijiazhuang City, China
| | - Nan Zhai
- Hebei Key Laboratory of Liver and Kidney Diseases of Integrated Traditional Chinese and Western Medicine 7th Floor, Scientific Research Building, Hebei University of Traditional Chinese Medicine, Shijiazhuang City, China
| | - Yan Zhong
- Hebei Key Laboratory of Liver and Kidney Diseases of Integrated Traditional Chinese and Western Medicine 7th Floor, Scientific Research Building, Hebei University of Traditional Chinese Medicine, Shijiazhuang City, China.
| | - Xiangting Wang
- Hebei Key Laboratory of Liver and Kidney Diseases of Integrated Traditional Chinese and Western Medicine 7th Floor, Scientific Research Building, Hebei University of Traditional Chinese Medicine, Shijiazhuang City, China.
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33
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Wu M, Sheng J, Xie Q, Qi Y, Zhao Y, Zhang S. Recent advances in stimuli-responsive hyaluronic acid-based nanodelivery systems for cancer treatment: A review. Int J Biol Macromol 2025; 316:144357. [PMID: 40403810 DOI: 10.1016/j.ijbiomac.2025.144357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 05/09/2025] [Accepted: 05/16/2025] [Indexed: 05/24/2025]
Abstract
Cancer is a worldwide public health problem that poses a serious threat to human health. Drug therapy, as the mainstay of cancer treatment, relies on carriers for the in vivo delivery of chemotherapeutic or nucleic acid-based drugs. Traditional drug delivery carriers have shortcomings, however, including a lack of targeting, uncontrollable release of drugs, and low stability, potentially leading to toxic side effects and reducing their antitumor efficacy. Advances in nanotechnology and biomedicine have furthered the development of stimuli-responsive nanodelivery systems, which can be used to realize the accumulation and on-demand release of drugs and reduce the required drug dosage and toxicity. Hyaluronic acid (HA), as a natural anionic polysaccharide with excellent biocompatibility, an easily modified structure, and the ability to target cancer cells, is a US Food and Drug Administration-approved biomaterial that is ideal for the construction of stimuli-responsive nanodelivery systems. Herein, we review HA-based stimuli-responsive nanodelivery systems including various HA-modified structures. We summarize the feasibility and effectiveness of these systems in cancer therapy according to their roles as endogenous- (pH, redox, enzyme, and hypoxia) or exogenous- (light, temperature, ultrasound, and magnetism) stimuli-responsive systems. We also discuss the problems and challenges in the development of HA-based stimuli-responsive nanodelivery systems and the perspectives for future development. This review highlights the great potential of HA-based stimuli-responsive nanodelivery systems for use in precision cancer treatment and controlled drug release.
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Affiliation(s)
- Mengdi Wu
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Jiabao Sheng
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China; Faculty of Health and Medicine, School of Medical Sciences, University of Sydney, Sydney, NSW 2050, Australia
| | - Qihan Xie
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Yanfei Qi
- Centenary Institute, The University of Sydney, Sydney, NSW 2050, Australia
| | - Yinan Zhao
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Shubiao Zhang
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China.
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34
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Zhang X, Nguyen MH. Metabolic dysfunction-associated steatotic liver disease: A sexually dimorphic disease and breast and gynecological cancer. Metabolism 2025; 167:156190. [PMID: 40081614 DOI: 10.1016/j.metabol.2025.156190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/26/2025] [Accepted: 03/09/2025] [Indexed: 03/16/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global public health and economic burden worldwide in the past few decades. Epidemiological studies have shown that MASLD is a multisystem disease that is associated not only with liver-related complications but also with an increased risk of developing extrahepatic cancers. MASLD is a sexually dimorphic disease with sex hormones playing an important role in the development and progression of MASLD, especially by the levels and ratios of circulating estrogens and androgens. MASLD is associated with hormone-sensitive cancers including breast and gynecological cancer. The risk of breast and gynecological cancer is elevated in individuals with MASLD driven by shared metabolic risk factors including obesity and insulin resistance. Multiple potential mechanisms underline these associations including metabolic dysfunction, gut dysbiosis, chronic inflammation and dysregulated release of hepatokines. However, the effect of hormone therapy including hormone replacement therapy and anti-estrogen treatment on MASLD and female-specific cancers remains debatable at this time. This synopsis will review the associations between MASLD and breast and gynecological cancer, their underlying mechanisms, implications of hormonal therapies, and their future directions.
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Affiliation(s)
- Xinrong Zhang
- Division of Gastroenterology and Hepatology, School of Medicine, Stanford University Medical Center, Palo Alto, CA, United States
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, School of Medicine, Stanford University Medical Center, Palo Alto, CA, United States; Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA, United States; Stanford Cancer Institute, Stanford University Medical Center, Palo Alto, CA, United States.
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35
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Wang K, Baird L, Yamamoto M. The clinical-grade CBP/ p300 inhibitor CCS1477 represses the global NRF2-dependent cytoprotective transcription program and re-sensitizes cancer cells to chemotherapeutic drugs. Free Radic Biol Med 2025; 233:102-117. [PMID: 40127850 DOI: 10.1016/j.freeradbiomed.2025.03.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/14/2025] [Accepted: 03/22/2025] [Indexed: 03/26/2025]
Abstract
Constitutive activation of NRF2 provides a selective advantage to malignant tumour clones through the hijacking of the NRF2-dependent cytoprotective transcriptional program, which allows the cancer cells to survive and thrive in the chemically stressful tumour niche, whilst also providing resistance to anti-cancer drugs due to the upregulation of xenobiotic metabolizing enzymes and drug efflux pumps. Through a small-molecule epigenetic screen carried out in KEAP1 mutant lung cancer cells, in this study, we identified CCS1477 (Inobrodib) to be an inhibitor of the global NRF2-dependent transcription program. Mechanistically, CCS1477 is able to repress NRF2's cytoprotective response through the inhibition of its obligate transcriptional activator partner CBP/p300. Importantly, in addition to repressing NRF2-dependent anti-oxidative stress and xenobiotic metabolizing enzyme gene expression, CCS1477 treatment is also able to reverse the chemoresistance phenotype and re-sensitize NRF2-activated tumour cells to anti-cancer drugs. Furthermore, in co-culture experiments of KEAP1 mutant cancer cells with primary human T cells, CCS1477 treatment suppressed the acquisition of the T cell exhaustion transcriptional state, which should function to augment the anti-cancer immune response. Thus, CCS1477-mediated inhibition of CBP/p300 represents a novel therapeutic strategy with which to target the currently untreatable tumours with aberrant NRF2 activation.
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Affiliation(s)
- Ke Wang
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan
| | - Liam Baird
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, Sendai, 980-8575, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Miyagi, Japan.
| | - Masayuki Yamamoto
- Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, Sendai, 980-8575, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Miyagi, Japan.
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Wan J, Shi JH, Shi M, Huang H, Zhang Z, Li W, Guo C, Bao R, Yu X, Han Q, Du X, Li S, Ye Y, Cui X, Li X, Li JH, Zou Q. Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8 + T cells. Nat Cell Biol 2025; 27:972-982. [PMID: 40461882 DOI: 10.1038/s41556-025-01673-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 04/16/2025] [Indexed: 06/19/2025]
Abstract
The aberrant accumulation of intracellular disulfides promotes cancer cell disulfidptosis; however, how disulfide stress influences tumour-infiltrating CD8+ T cell function remains unknown. Here we demonstrate that lactate dehydrogenase B (LDHB) facilitates intratumoural CD8+ T cell disulfidptosis and exhaustion, leading to impaired antitumour immunity. SLC7A11-mediated cystine uptake by CD8+ T cells induces disulfidptosis, which plays critical roles in the development of exhausted CD8+ T cells. LDHB restricts glucose-6-phosphate dehydrogenase (G6PD) activity in exhausted CD8+ T cells by interacting with G6PD, causing NADPH depletion and consequently triggering disulfidptosis. Accordingly, the loss of LDHB in T cells prevents disulfidptosis-dependent CD8+ T cell exhaustion and improves antitumour immunity. Mechanistically, STAT3 directs LDHB expression to limit G6PD activity and mediate disulfidptosis in exhausted CD8+ T cells. Our results highlight the distinct roles of disulfidptosis and ferroptosis in driving CD8+ T cell exhaustion and suggest a potential therapeutic strategy to target LDHB in cancer immunotherapy.
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Affiliation(s)
- Jie Wan
- Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian-Hong Shi
- Central Laboratory, Hebei International Joint Research Center for Digital Twin Diagnosis and Treatment of Digestive Tract Tumors, Affiliated Hospital of Hebei University, Baoding, China
| | - Min Shi
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haiyan Huang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhen Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenyan Li
- Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenyue Guo
- Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rujuan Bao
- Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoyan Yu
- Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiaoqiao Han
- Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xian Du
- Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Song Li
- Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Youqiong Ye
- Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xingang Cui
- Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Xia Li
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Jing-Hua Li
- Department of Hepatobiliary Surgery, Baoding Key Laboratory of Precision Diagnosis and Treatment of Digestive Tract Tumors, Affiliated Hospital of Hebei University, Baoding, China.
| | - Qiang Zou
- Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Yang W, Zhu Z, Zhou C, Chen J, Ou J, Tong H, Iyaswamy A, Chen P, Wei X, Yang C, Xiao W, Wang J, Zhang W. The rheumatoid arthritis drug Auranofin targets peroxiredoxin 1 and peroxiredoxin 2 to trigger ROS-endoplasmic reticulum stress axis-mediated cell death and cytoprotective autophagy. Free Radic Biol Med 2025; 233:1-12. [PMID: 40089079 DOI: 10.1016/j.freeradbiomed.2025.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/26/2025] [Accepted: 03/12/2025] [Indexed: 03/17/2025]
Abstract
Auranofin (AF) is a gold-based compound and it has been used in the treatment of rheumatoid arthritis for over four decades. Recently, it has been demonstrated to show significant antitumor activity across various cancer types and is being repurposed as an anticancer drug. However, the precise mechanisms underlying its antitumor effects, particularly its binding targets, remain poorly understood. Here, we demonstrate that Auranofin (AF) exerts cytotoxic effects in 786-O renal cancer cells via inducing apoptosis. Mechanistic studies reveal that AF induces reactive oxygen species (ROS) accumulation, which is a key factor in mediating AF-induced stress and subsequently apoptosis. Notably, both ROS and ER stress induce autophagy, and inhibition of autophagy further enhances AF-induced cytotoxicity. Interestingly, activity-based protein profiling (ABPP) analysis identifies two key antioxidant enzymes, peroxiredoxin 1 (PRDX1) and peroxiredoxin 2 (PRDX2), as direct binding targets of AF. Importantly, overexpression of PRDX1 or PRDX2 inhibits AF-induced ROS accumulation and subsequent apoptosis. Overall, our findings demonstrate that AF induces apoptosis by covalently binding to PRDX1/2 to inhibit its activity, leading to ROS accumulation, which triggers ER stress and apoptosis. At the same time, ER stress triggers a cytoprotective autophagic response. These findings provide novel insights into the mechanism of AF-induced cytotoxicity and suggest PRDX1/2 as critical targets for the development of anti-renal cancer therapies.
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Affiliation(s)
- Wenyue Yang
- The First Affiliated Hospital/The First Clinical Medicine School of Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Zhou Zhu
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Chaohua Zhou
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Junhui Chen
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Jinhuan Ou
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Haibo Tong
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Ashok Iyaswamy
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region of China; Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, India
| | - Peng Chen
- Experimental Research Center, China Academy of Traditional Chinese Medicine, Beijing, 100700, China
| | - Xu Wei
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Chuanbin Yang
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Wei Xiao
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China.
| | - Jigang Wang
- The First Affiliated Hospital/The First Clinical Medicine School of Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China; Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China; Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Wei Zhang
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China.
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Xu L, Lei Z, Wang Q, Jiang Q, Xing B, Li X, Guo X, Wang Z, Li S, Huang Y, Lei T. Androgen Receptor Mediates Dopamine Agonist Resistance by Regulating Intracellular Reactive Oxygen Species in Prolactin-Secreting Pituitary Adenoma. Antioxid Redox Signal 2025; 42:954-972. [PMID: 39360800 DOI: 10.1089/ars.2024.0611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2024]
Abstract
Aims: Dopamine agonists (DAs) are the first-line treatment for patients with prolactin-secreting pituitary adenoma (PRL adenoma). However, a subset of individuals exhibits poor responses, known as DA resistance. Previous studies have reported that DA resistance is more prevalent in male patients. This study aims to investigate the relationship between androgen receptor (AR) expression and DA resistance, as well as to explore underlying mechanisms of AR-mediated DA resistance. Results: Our results demonstrated that patients with higher AR expression exhibit greater resistance to DA in our cohort of DA-resistant PRL adenoma. Furthermore, AR was found to be involved in cell proliferation, PRL secretion, and resistance to bromocriptine (BRC) both in vitro and in vivo. Mechanistically, we demonstrated that intracellular reactive oxygen species (ROS) function as upstream mediators of apoptosis and ferroptosis following BRC treatment. As a ligand-dependent transcription factor, AR could translocate to the nucleus and transcriptionally promote NFE2-like bZIP transcription factor 2 (NRF2) expression, which regulates intracellular ROS levels, thereby enhancing cell viability and conferring DA resistance to pituitary adenoma (PA) cells. Finally, AR targeting agents were used to inhibit AR signaling, downregulate NRF2 transcription, and sensitize PA cells to BRC treatment. Conclusion and Innovation: We demonstrated that AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas. Antioxid. Redox Signal. 42, 954-972.
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Affiliation(s)
- Linpeng Xu
- Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuowei Lei
- Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
- Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Quanji Wang
- Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Jiang
- Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Biao Xing
- Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Xingbo Li
- Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Xiang Guo
- Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Zihan Wang
- Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Sihan Li
- Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Yimin Huang
- Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Lei
- Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China
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Ngo HV, Nguyen HD, Lee BJ. Triple synergistic cancer targeting strategies utilizing redox-sensitive fattigated hyaluronic acid nanoparticles encapsulating doxorubicin. Int J Biol Macromol 2025; 313:144168. [PMID: 40379189 DOI: 10.1016/j.ijbiomac.2025.144168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/30/2025] [Accepted: 05/11/2025] [Indexed: 05/19/2025]
Abstract
Antitumor potentials of dietary oleic acid (OA), primarily through enhancing intracellular lipid accumulation in various human cancers are hindered by poor selectivity and tumor targetability. Cancer cells are also challenged by high concentration of glutathione (GSH) and favorable binding affinity of hyaluronic acid (HA) to the CD44 (acidic cell surface adhesion protein) receptor. A novel conjugate (HA-CYS-OA, HOC) was synthesized by linking GSH-sensitive cystamine (CYS) to OA and HA. This amphiphilic HOC could self-assemble into redox-sensitive nanoparticles (HON) to co-deliver OA and encapsulated doxorubicin (DOX). HON synergistically enhanced anticancer efficacy by facilitating HA-mediated cellular uptake and GSH-triggered OA release in a targeted manner. Encapsulation of DOX in HON resulted in higher cellular uptake and more efficient DOX release compared to the commercially available liposomal DOX formulation. Furthermore, DOX-HON protected non-cancerous cells, while significantly increasing cytotoxicity and higher rate of apoptosis of human breast carcinoma cells, demonstrating superior selectivity indices. This enhanced performance was attributed to the triple synergistic actions of HA-mediated DOX targeting and OA-induced lipid accumulation from the redox-sensitive nanoformulation. Collectively, our results suggested that enzyme specific HON could be a bioactive and selective nanocarrier model for the co-delivery of fatty acids and chemotherapeutic drugs in synergistic cancer therapy.
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Affiliation(s)
- Hai Van Ngo
- Department of Pharmacy, College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea; Drug Delivery and Disposition, KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Campus Gasthuisberg ON2, Herestraat 49 b921, 3000 Leuven, Belgium
| | - Hy Dinh Nguyen
- Department of Pharmacy, College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea
| | - Beom-Jin Lee
- Department of Pharmacy, College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea; Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea.
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Liu Y, Wu G, Feng L, Li J, Xia Y, Guo W, Zhao K. Harnessing Antioxidants in Cancer Therapy: Opportunities, Challenges, and Future Directions. Antioxidants (Basel) 2025; 14:674. [PMID: 40563308 DOI: 10.3390/antiox14060674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2025] [Revised: 05/27/2025] [Accepted: 05/29/2025] [Indexed: 06/28/2025] Open
Abstract
Antioxidants neutralize reactive oxygen species and free radicals, protecting cells from oxidative damage and maintaining cellular homeostasis. In cancer therapy, they play a complex dual role, serving as protective agents against oxidative stress while, under certain conditions, acting as pro-oxidants that may promote tumorigenesis and resistance to treatment. Redox regulation is governed by key antioxidant pathways, such as the BACH1 and NRF2 pathways, along with transcriptional factors that significantly affect cancer progression and immunotherapy response. In addition to their intracellular effects, antioxidants modulate the tumor microenvironment, including interactions with the extracellular matrix, which impact cancer cell behavior and therapeutic responses. This review also explores preclinical studies that investigate the roles of major antioxidants in cancer biology. While these studies present promising data, significant challenges persist, including the potential for antioxidants to interfere with standard cancer treatments or to inadvertently support tumor survival. We further highlight emerging strategies aimed at optimizing antioxidant therapy, including personalized medicine approaches, nanoparticle-based delivery systems, and combination treatments with immunotherapies and targeted therapies. By examining the therapeutic potential and associated risks of antioxidants, this review provides critical insights into their role in cancer treatment and offers a roadmap for advancing antioxidant-based strategies to improve clinical outcomes.
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Affiliation(s)
- Yu'e Liu
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
- Boston Children's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Guangzhen Wu
- Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Linjing Feng
- Department of Oncology Surgery, Shanghai Mengchao Cancer Hospital, Shanghai University, Shanghai 201800, China
| | - Jialing Li
- University of Illinois College of Medicine Rockford Family Medicine, Rockford, IL 61104, USA
| | - Yuyang Xia
- School of Medicine, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Wenjia Guo
- Department of Laboratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Kaijun Zhao
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
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41
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Li Z, Lu Y, Wang L, Shi L, Wang T. Reactive oxygen species-dependent nanomedicine therapeutic modalities for gastric cancer. NANOSCALE ADVANCES 2025; 7:3210-3227. [PMID: 40308560 PMCID: PMC12038724 DOI: 10.1039/d5na00321k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2025] [Accepted: 04/15/2025] [Indexed: 05/02/2025]
Abstract
Reactive oxygen species (ROS) play a double-edged role in gastric cancer (GC). Higher levels of ROS in tumor cells compared to normal cells facilitate tumor progression. Once ROS concentrations rise rapidly to toxic levels, they cause GC cell death, which is instead beneficial for GC treatment. Based on these functions, nano-delivery systems taking the therapeutic advantages of ROS have been widely employed in tumor therapy in recent years, overcoming the drawbacks of conventional drug delivery techniques, such as non-specific systemic effects. In this review, the precise impacts of ROS on GC have been detailed, along with ROS-based nanomedicine therapeutic schemes. These strategies mainly focused on the use of excess ROS in the tumor microenvironment for controlled drug release and a substantial enhancement of ROS concentrations for tumor killing. The challenges and opportunities for the advancement of these anticancer therapies are also emphasized.
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Affiliation(s)
- Zhiyan Li
- Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
| | - Yanjun Lu
- Division of Gastric Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
| | - Lulu Wang
- Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
| | - Liuyi Shi
- Yangzhou University Medical College Yangzhou 225001 China
| | - Tao Wang
- Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
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42
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Niu Y, Zhao T, Wang X, Sun Y, Zhang Y. Molecular Dynamics Simulations of Plasma-Antifolate Drug Synergy in Cancer Therapy. Biomolecules 2025; 15:773. [PMID: 40563414 DOI: 10.3390/biom15060773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2025] [Revised: 05/13/2025] [Accepted: 05/22/2025] [Indexed: 06/28/2025] Open
Abstract
Reactive oxygen species (ROS) generated by cold atmospheric plasma (CAP) cause irreversible damage to cancer cell DNA, RNA, mitochondria, and antioxidant defense systems, leading to apoptosis. Plasma-induced disruption of the antioxidant defense system of cancer cells by cystine uptake via xC- antiporter has been widely studied, while folate uptake by cancer cells via high expression of hSLC19A1, which generates Nicotinamide Adenine Dinucleotide Phosphate (NADPH) via one-carbon metabolism, is also an important component of the antioxidant defense mechanism of cancer cells. Disrupting folate transport in cancer cells is an important potential pathway for synergizing with pemetrexed (PMX) to induce apoptosis in cancer cells, which is of great research value. In this paper, classical molecular dynamics simulations were employed to study the effect of plasma oxidation of hSLC19A1 on the uptake of 5-Methyltetrahydrofolate (5-MTHF), which is the predominant dietary and circulatory folate, and the antifolate chemotherapeutic agent PMX by cancer cells. The results showed that the channel radius of hSLC19A1 for transporting 5MTHF after oxidation became narrower and the conformation tended to be closed, which was unfavorable for the transport of 5-MTHF; hydrogen bonding and hydrophobic interactions between hSLC19A1 and 5-MTHF decreased, the predicted docking affinity decreased, and the binding energy decreased from -28.023 kcal/mol to -16.866 kcal/mol, while that with PMX was stable around -28 kcal/mol, suggesting that the oxidative modification reduced the binding capacity of hSLC19A1 and 5-MTHF while barely affecting the transport of PMX, which contributed to weakening the antioxidant defense system of cancer cells and synergizing with PMX to induce apoptosis in cancer cells. Our simulations provide theoretical insights for CAP-induced apoptosis in cancer cells at the microscopic level and help promote the further development of cold atmospheric plasma in the field of cancer therapy.
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Affiliation(s)
- Yanxiong Niu
- School of Electrical Engineering, Shandong University, Ji'nan 250061, China
| | - Tong Zhao
- School of Electrical Engineering, Shandong University, Ji'nan 250061, China
| | - Xiaolong Wang
- School of Electrical Engineering, Shandong University, Ji'nan 250061, China
| | - Ying Sun
- School of Electrical Engineering, Shandong University, Ji'nan 250061, China
| | - Yuantao Zhang
- School of Electrical Engineering, Shandong University, Ji'nan 250061, China
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Li N, Xu J, Liu B, Elango J, Wu W. Highly Soluble Mussel Foot Protein Enhances Antioxidant Defense and Cytoprotection via PI3K/Akt and Nrf2/HO-1 Pathways. Antioxidants (Basel) 2025; 14:644. [PMID: 40563279 DOI: 10.3390/antiox14060644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2025] [Revised: 05/22/2025] [Accepted: 05/26/2025] [Indexed: 06/28/2025] Open
Abstract
Mussel foot protein is a bioadhesive protein with potential biomedical applications, but its limited solubility and poor biological stability hinder its widespread use. In this study, highly soluble mussel foot protein (HMFP) was successfully extracted using a stepwise selective enzymatic digestion method, with a molecular weight in the range of 11-17 kDa. Furthermore, a dual-functional polyethylene glycol (PEG) derivative of HMFP, designated HMFP-PEG, was synthesized. FTIR analysis confirmed the successful modification of HMFP with PEG, while TGA analysis and SEM observations demonstrated that PEG modification significantly enhanced the stability of the protein. Both HMFP and HMFP-PEG effectively scavenged free radicals, enhanced antioxidant enzyme activity, and reduced MDA levels. Additionally, they activated the PI3K/Akt and Nrf2/HO-1 signaling pathways, inhibiting H2O2-induced cell apoptosis. Notably, HMFP-PEG exhibited superior antioxidant and cell-protective effects compared to HMFP, suggesting that PEG modification improves the functional stability of the protein. This study provides theoretical support for the potential application of HMFP in the biomedical and tissue engineering fields.
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Affiliation(s)
- Na Li
- Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Jiren Xu
- Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Boheng Liu
- Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Jeevithan Elango
- Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
- Department of Biomaterials Engineering, Faculty of Health Sciences, UCAM-Universidad Católica San Antonio de Murcia, Guadalupe, 30107 Murcia, Spain
| | - Wenhui Wu
- Department of Marine Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
- Marine Biomedical Science and Technology Innovation Platform of Lin-gang Special Area, Shanghai 201306, China
- Putuo Branch of International Combined Research Center for Marine Biological Sciences, Zhoushan 316104, China
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Ungureanu D, Marc G, Tiperciuc B, Moldovan C, Ionuț I, Stana A, Oniga I, Vlase L, Pîrnău A, Oniga O. Novel 3,4-Dihydroxyphenyl-Thiazole-Coumarin Hybrid Compounds: Synthesis, In Silico and In Vitro Evaluation of Their Antioxidant Activity. Antioxidants (Basel) 2025; 14:636. [PMID: 40563271 DOI: 10.3390/antiox14060636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2025] [Revised: 05/22/2025] [Accepted: 05/23/2025] [Indexed: 06/28/2025] Open
Abstract
Oxidative stress represents a key process in many physiopathological mechanisms involved in several diseases. Therefore, antioxidants represent an important strategy in reversing this pathologic process. In the present study, we proposed the design, synthesis, computational, and in vitro evaluation of seven novel hydroxyphenyl-thiazole-coumarin hybrid compounds (4a-g) as antioxidant molecules. The conducted theoretical quantum and thermodynamical calculations revealed compound 4f as the most promising antioxidant, having the highest HOMO-LUMO gaps (3.13 eV in vacuum, 3.22 eV in nonpolar environment, and 3.33 in water) and some of the lowest BDE values (68.23 kcal/mol and 69.63 kcal/mol for O-H and N-H bonds in nonpolar environment). This was transposed in the results obtained following the in vitro antiradical (DPPH• and ABTS•+) and electron transfer capacity assays (TAC, RP, FRAP, and CUPRAC), although all compounds showed important antioxidant activity, superior in almost all instances to ascorbic acid and Trolox, which were used as references. Compounds 4f and 4g can serve as molecules for further research involving in vivo antioxidant activity and possible synergistic mechanisms.
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Affiliation(s)
- Daniel Ungureanu
- Department of Pharmaceutical Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, 400012 Cluj-Napoca, Romania
| | - Gabriel Marc
- Department of Organic Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, 400012 Cluj-Napoca, Romania
| | - Brîndușa Tiperciuc
- Department of Pharmaceutical Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, 400012 Cluj-Napoca, Romania
| | - Cristina Moldovan
- Department of Pharmaceutical Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, 400012 Cluj-Napoca, Romania
| | - Ioana Ionuț
- Department of Pharmaceutical Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, 400012 Cluj-Napoca, Romania
| | - Anca Stana
- Department of Pharmaceutical Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, 400012 Cluj-Napoca, Romania
| | - Ilioara Oniga
- Department of Pharmacognosy, "Iuliu Hațieganu" University of Medicine and Pharmacy, 12 Ion Creangă Street, 400010 Cluj-Napoca, Romania
| | - Laurian Vlase
- Department of Pharmaceutical Technology and Biopharmacy, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, 400012 Cluj-Napoca, Romania
| | - Adrian Pîrnău
- National Institute for Research and Development of Isotopic and Molecular Technologies, 67-103 Donath Street, 400293 Cluj-Napoca, Romania
| | - Ovidiu Oniga
- Department of Pharmaceutical Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, 400012 Cluj-Napoca, Romania
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Stojanović TD, Rakić MR, Ćosić MV, Oalđe Pavlović MM, Sabovljević AD, Sabovljević MS, Božić BĐ, Božić Nedeljković BĐ, Vujičić MM, Lunić TM. Moss Extracts as Natural Neuroprotective Agents: Mitigating LPS-Induced Neuroinflammation and Microglial Activation. Cells 2025; 14:780. [PMID: 40497956 PMCID: PMC12153916 DOI: 10.3390/cells14110780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2025] [Revised: 05/20/2025] [Accepted: 05/23/2025] [Indexed: 06/19/2025] Open
Abstract
Neuroinflammation plays a central role in the pathogenesis of neurodegenerative diseases, and there is increasing interest in identifying natural compounds with anti-neuroinflammatory and neuroprotective effects. In this study, we aimed to investigate the biological activities of ethanol and ethyl acetate extracts from five moss species (Dicranum scoparium, Fontinalis antipyretica, Hypnum cupressiforme, Polytrichum formosum, and Tortella tortuosa) with a focus on their neuroprotective and anti-neuroinflammatory potential. Phytochemical profiling revealed the presence of phenols (up to 24.77 mg GAE/g), phenolic acids (up to 235.48 mg CAE/g), and triterpenoids (up to 367.98 mg UAE/g). A series of in vitro assays, including acetylcholinesterase (AChE) and tyrosinase inhibition, MTT, NBT, Griess, and ELISA, were used to assess their bioactivity. Several extracts, particularly ethanolic, significantly inhibited AChE activity, while tyrosinase inhibition was moderate and concentration-dependent. Most extracts maintained >85% cell metabolic activity in BV2 mouse microglia and L929 mouse fibroblasts. Moss extracts significantly suppressed lipopolysaccharide (LPS)-induced production of reactive oxygen species (ROS), nitric oxide (NO), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) in BV2 cells and reduced microglia-mediated neurotoxicity in undifferentiated SH-SY5Y cells. These findings indicate that moss-derived extracts possess promising anti-neuroinflammatory and neuroprotective properties that warrant further investigation.
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Affiliation(s)
- Tijana D. Stojanović
- Public Company “Nuclear Facilities of Serbia”, 11000 Belgrade, Serbia;
- Institute of Physiology and Biochemistry “Ivan Djaja”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (M.R.R.); (B.Đ.B.); (B.Đ.B.N.)
- Institute of Botany and Botanical Garden “Jevremovac”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia (M.M.O.P.); (A.D.S.); (M.S.S.)
| | - Marija R. Rakić
- Institute of Physiology and Biochemistry “Ivan Djaja”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (M.R.R.); (B.Đ.B.); (B.Đ.B.N.)
| | - Marija V. Ćosić
- Institute of Botany and Botanical Garden “Jevremovac”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia (M.M.O.P.); (A.D.S.); (M.S.S.)
| | - Mariana M. Oalđe Pavlović
- Institute of Botany and Botanical Garden “Jevremovac”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia (M.M.O.P.); (A.D.S.); (M.S.S.)
| | - Aneta D. Sabovljević
- Institute of Botany and Botanical Garden “Jevremovac”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia (M.M.O.P.); (A.D.S.); (M.S.S.)
| | - Marko S. Sabovljević
- Institute of Botany and Botanical Garden “Jevremovac”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia (M.M.O.P.); (A.D.S.); (M.S.S.)
- Department of Plant Biology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Mánesova 23, 04001 Košice, Slovakia
| | - Bojan Đ. Božić
- Institute of Physiology and Biochemistry “Ivan Djaja”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (M.R.R.); (B.Đ.B.); (B.Đ.B.N.)
| | - Biljana Đ. Božić Nedeljković
- Institute of Physiology and Biochemistry “Ivan Djaja”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (M.R.R.); (B.Đ.B.); (B.Đ.B.N.)
| | - Milorad M. Vujičić
- Institute of Botany and Botanical Garden “Jevremovac”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia (M.M.O.P.); (A.D.S.); (M.S.S.)
| | - Tanja M. Lunić
- Institute of Physiology and Biochemistry “Ivan Djaja”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (M.R.R.); (B.Đ.B.); (B.Đ.B.N.)
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Wu D, Zhang S, Wu Y, Bi X, Zhou Y, Wu W. Sulforaphane downregulates mitochondrial TIGAR via inhibiting mitochondrial transmembrane assembly and LONP1/CASP3 axis causing apoptosis. Biochem Biophys Res Commun 2025; 760:151689. [PMID: 40157290 DOI: 10.1016/j.bbrc.2025.151689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/17/2025] [Accepted: 03/23/2025] [Indexed: 04/01/2025]
Abstract
TP53-induced glycolysis and apoptosis regulator (TIGAR) was implicated to be a brand-new target for sulforaphane (SFN) in human non-small cell lung cancer (NSCLC), while the mechanism was elusive. We found that highly expressed TIGAR was positively correlated to pathological grading and contributed to poor survival in NSCLC patients. Western blot showed that SFN downregulated α-tubulin, TIGAR, Timm23 and Timm17A in cytosolic and/or mitochondrial lysate. Besides, SFN downregulated α-tubulin contributing to TIGAR reduction, and also decreased interactions of α-tubulin to Timm23, Timm17A and TIGAR in mitochondria; thus, SFN disrupted the microtubule-mediated mitochondrial transmembrane complexes blocking the entry of cytosolic TIGAR into mitochondria. Further, SFN downregulated mitoprotease LONP1 and decreased the binding of LONP1 to TIGAR; knockdown of LONP1 activated mitochondrial caspase-3 causing the cleavage of mitochondrial TIGAR; SFN-mediated the reduction of TIGAR decreased NADPH leading to ROS elevation and apoptosis in NSCLC. These studies will provide key targets for anti-NSCLC therapy.
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Affiliation(s)
- Dongxue Wu
- Neonatal Intensive Care Unit, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Sitian Zhang
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yaheng Wu
- Department of Education, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Xiaoyu Bi
- Core Facility, Capital Medical University, Beijing, China
| | - Yan Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
| | - Wei Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
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47
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Chen Y, Tian Y, Guan B, Chang Y, Yan X, Song Q, Chen W, Chen L, Li W, Mao W, Zhang Y, Chen C, Li S. Morinda officinalis oligosaccharides attenuate mitochondria-associated ferroptosis via the NOX4/mitoGPX4 pathway in myocardial ischemia‒reperfusion injury. Front Cell Dev Biol 2025; 13:1605513. [PMID: 40491951 PMCID: PMC12146387 DOI: 10.3389/fcell.2025.1605513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Accepted: 05/06/2025] [Indexed: 06/11/2025] Open
Abstract
Aim To explore the benefits of Morinda officinalis oligosaccharides (MOO) on ischemia-reperfusion (I/R) injury and the possible mechanisms involved. Methods Myocardial I/R injury were induced by left anterior descending branch ligation. MOO pretreatment was given orally 2 weeks prior to ischemic treatment. Echocardiograms, biochemical parameters, and histological and immunohistochemical analyses were used to determine the benefits of MOO on myocardial I/R injury. Oxidative stress and ferroptosis were examined by biochemical parameters, Western blot, immunohistochemistry, and Tunel staining. Results MOO improved cardiac function and reduced myocardial oxidative stress and ferroptosis, which was associated with the inhibition of NADPH Oxidase 4 (NOX4) expression. Whereas, the upregulation of NOX4 abolished the benefits of MOO. Furthermore, MOO enhanced mitochondrial superoxide dismutase 2 (SOD2) activity and stimulated the mitochondrial translocation of glutathione peroxidase 4 (mitoGPX4) by inhibiting NOX4. Mitochondria-specific GPX4 overexpression attenuated mitochondrial oxidative stress and suppressed mitochondria-associated ferroptosis in cardiomyocytes that suffered from hypoxia-reoxygenation (H/R) injury, even after NOX4 overexpression. Conclusion These results indicate the beneficial effects of MOO on myocardial I/R injury by suppressing oxidative stress and mitochondria-associated ferroptosis through NOX4/mitoGPX4 pathway.
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Affiliation(s)
- Yuqiong Chen
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Yuan Tian
- Department of Cardiology, Jinshan Hospital, Fudan University, Shanghai, China
| | - Bo Guan
- Department of Geriatrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Yiling Chang
- The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Xiaopei Yan
- Department of Respiratory Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Qi Song
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Wenting Chen
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Lin Chen
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Wei Li
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Wenjun Mao
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Yan Zhang
- Department of Anesthesiology, Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Nanjing Medical University, Xuzhou, China
| | - Chao Chen
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Su Li
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China
- National Clinical Research Center for Interventional Medicine, Shanghai, China
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48
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Liu P, Chen Y. Integrative Analysis of EPHX4 as a Novel Prognostic and Diagnostic Biomarker in Lung Adenocarcinoma. Int J Mol Sci 2025; 26:5095. [PMID: 40507905 PMCID: PMC12154108 DOI: 10.3390/ijms26115095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2025] [Revised: 05/22/2025] [Accepted: 05/23/2025] [Indexed: 06/16/2025] Open
Abstract
Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, necessitating the identification of novel biomarkers for improved prognosis and diagnosis. This study investigates the role of epoxide hydrolase 4 (EPHX4), a member of the epoxide hydrolase family, in LUAD. Using data sourced from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, which were subsequently validated by the Gene Expression Omnibus (GEO), we analyzed levels of EPHX4 expression, mutation, and methylation in tumors versus normal tissues. Our findings revealed a significant upregulation of EPHX4 in LUAD tissues compared to normal lung tissues (p < 0.001), correlating with poorer overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). Furthermore, EPHX4 exhibited considerable diagnostic potential, as demonstrated by an area under the curve (AUC) of 0.854 in a Receiver Operating Characteristic (ROC) analysis. Notably, EPHX4 expression was associated with immune infiltration, specifically Th2 cells, neutrophils, and macrophages, along with immune checkpoint molecules including PD-L1, PD-L2, and TIM-3. Additionally, EPHX4 was involved in pivotal tumor-associated pathways, particularly cell cycle regulation. In conclusion, an elevated EPHX4 expression is indicative of poorer prognosis in LUAD and may play a role in immune evasion and cell cycle dysregulation, highlighting its potential as a promising biomarker for the diagnosis and prognostic prediction of LUAD.
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Affiliation(s)
- Pengze Liu
- Department of Pathology, School of Medicine, Jinan University, Guangzhou 510632, China;
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China
| | - Yutong Chen
- Department of Pathology, School of Medicine, Jinan University, Guangzhou 510632, China;
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49
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Caller T, Moore KJ, Lehmann LH, Wu SM, Leor J. Insights Into Heart-Tumor Interactions in Heart Failure. Circ Res 2025; 136:1262-1285. [PMID: 40403117 DOI: 10.1161/circresaha.124.325490] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 02/10/2025] [Accepted: 02/27/2025] [Indexed: 05/24/2025]
Abstract
Heart failure (HF) often coexists with cancer. Beyond the known cardiotoxicity of some cancer treatments, HF itself has been associated with increased cancer incidence. The 2 conditions share common risk factors, mechanisms, and interactions that can worsen patient outcomes. The bidirectional relationship between HF and cancer presents a complex interplay of factors that are not fully understood. Recent preclinical evidence suggests that HF may promote tumor growth via the release of protumorigenic factors from the injured heart, revealing HF as a potentially protumorigenic condition. Our review discusses the biological crosstalk between HF and cancer, emphasizing the impact of HF on tumor growth, with inflammation, and modulating the immune system as central mechanisms. We further explore the clinical implications of this connection and propose future research directions. Understanding the mechanistic overlap and interactions between HF and cancer could lead to new biomarkers and therapies, addressing the growing prevalence of both conditions and enhancing approaches to diagnosis, prevention, and treatment.
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Affiliation(s)
- Tal Caller
- Neufeld and Tamman Cardiovascular Research Institutes, Faculty of Medical and Health Sciences, Tel Aviv University, Israel (T.C., J.L.)
- Lev Leviev Cardiovascular and Thoracic Center, Sheba Medical Center, Tel Hashomer, Israel (T.C., J.L.)
| | - Kathryn J Moore
- Department of Medicine, Cardiovascular Research Center, New York University Grossman School of Medicine (K.J.M.)
| | - Lorenz H Lehmann
- Department of Cardiology, University Hospital Heidelberg, Germany (L.H.L.)
- German Center of Cardiovascular Research (DZHK), Partnersite Heidelberg/Mannheim, Germany (L.H.L.)
- German Cancer Research Center (DKFZ), Heidelberg, Germany (L.H.L.)
| | - Sean M Wu
- Stanford Cardiovascular Institute (S.M.W.), Stanford University School of Medicine, CA
- Division of Cardiovascular Medicine, Department of Medicine (S.M.W.), Stanford University School of Medicine, CA
| | - Jonathan Leor
- Neufeld and Tamman Cardiovascular Research Institutes, Faculty of Medical and Health Sciences, Tel Aviv University, Israel (T.C., J.L.)
- Lev Leviev Cardiovascular and Thoracic Center, Sheba Medical Center, Tel Hashomer, Israel (T.C., J.L.)
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50
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Liu B, Zhou F, Shi B, Yan Y, Wang Y, Wang J, Lang Y, Xu S. Peptide YY fragment PYY1-36 disrupts mitochondrial biogenesis via RBM43-dependent PGC-1α translation inhibition. Invest New Drugs 2025:10.1007/s10637-025-01545-4. [PMID: 40404898 DOI: 10.1007/s10637-025-01545-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Accepted: 05/08/2025] [Indexed: 05/24/2025]
Abstract
Mitochondrial dysfunction is a key driver of cancer progression, with therapies increasingly targeting metabolic weaknesses. Peptide YY (PYY), a gastrointestinal hormone, regulates cellular activity, but its influence on mitochondrial health in lung cancer remains poorly understood. We explored how PYY1-36, a bioactive fragment of PYY, affects mitochondrial stability in NCI-H1581 lung cancer cells. Using dose-response experiments, we measured oxidative stress by tracking lactate dehydrogenase (LDH) release, mitochondrial ROS levels, and oxidative DNA damage (8-OHdG). Energy production was evaluated through ATP levels, oxygen consumption rates (OCR), and Complex I activity. We also analyzed mitochondrial biogenesis markers (NRF1, TFAM, PGC-1α) and the RNA-binding protein RBM43 via qPCR and immunoblotting. Dose-dependent tests showed that PYY1-36 triggers mitochondrial oxidative damage, marked by higher LDH release and ROS spikes. These changes aligned with sharp drops in ATP production and disrupted respiratory function. Notably, PYY1-36 reduced mitochondrial mass and biogenesis, supported by weaker MitoTracker Red signals and lower mtDNA/nDNA ratios. Key regulators NRF1 and TFAM were strongly suppressed, pointing to widespread mitochondrial failure. Intriguingly, PYY1-36 blocked PGC-1α protein synthesis without altering mRNA levels, suggesting a post-transcriptional control mechanism. PYY1-36 also boosted RBM43 levels. Knocking down RBM43 reversed PYY1-36's effects on PGC-1α and mitochondrial health. Our findings reveal RBM43 as a central player in PYY1-36-induced mitochondrial dysfunction through its suppression of PGC-1α translation. Targeting RBM43 could unlock new strategies to tackle metabolic chaos in lung cancer.
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Affiliation(s)
- Benkun Liu
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Fucheng Zhou
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Bowen Shi
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Yubo Yan
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Yanbo Wang
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Junfeng Wang
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Yaoguo Lang
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China
| | - Shidong Xu
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China.
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