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Gao C, Li J, Shan B. Research progress on the regulatory role of lactate and lactylation in tumor microenvironment. Biochim Biophys Acta Rev Cancer 2025; 1880:189339. [PMID: 40311713 DOI: 10.1016/j.bbcan.2025.189339] [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: 11/27/2024] [Revised: 04/26/2025] [Accepted: 04/28/2025] [Indexed: 05/03/2025]
Abstract
The tumor microenvironment (TME) arises from the dynamic interactions between tumor cells and the surrounding medium, including a variety of cell types and extracellular components, which have an important impact on the genesis and development of tumors. A key player in TME is lactate, a metabolic byproduct of glycolysis, which serves as a significant energy source. Lactate has direct implications on the survival and differentiation of immune cells, the metabolic reprogramming and progression of tumor cells. Moreover, lactylation, a unique post-translational modification, exerts a regulatory effect on TME by affecting gene transcription via adding lactate groups to both histone and non-histone proteins. This review systematically and comprehensively synthesizes emerging evidence on how the lactate-lactylation axis drives immune evasion, therapy resistance, and TME remodeling, highlighting the therapeutic targets related to lactate and lactylation that dismantle this metabolic-epigenetic crosstalk.
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Affiliation(s)
- Chunyan Gao
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Prevention, Precision Diagnosis and Treatment of Hebei, Clinical Oncology Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China
| | - Jiali Li
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Prevention, Precision Diagnosis and Treatment of Hebei, Clinical Oncology Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China
| | - Baoen Shan
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Prevention, Precision Diagnosis and Treatment of Hebei, Clinical Oncology Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China.
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2
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Caini P, Carloni V. Metabolism and Immune Suppressive Response in Liver Cancer. Biomedicines 2025; 13:1461. [PMID: 40564180 DOI: 10.3390/biomedicines13061461] [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: 03/01/2025] [Revised: 05/27/2025] [Accepted: 06/11/2025] [Indexed: 06/28/2025] Open
Abstract
Hepatocellular carcinoma (HCC) constitutes more than 90% of the primary tumor of the liver. Metabolic reprogramming is decisive in promoting HCC development. The new metabolic program drives the surrounding immune cells to an immune suppressive commitment, enabling tumor survival. The enhanced metabolic activity of cancer cells leads to competition for essential nutrients, depriving non-malignant cells of critical resources. Simultaneously, the accumulation of metabolic byproducts within the tumor microenvironment (TME) selectively favors innate immune responses while impairing adaptive immunity. Recent advances in cancer immunotherapy underscore the importance of targeting both immune cell function and metabolic pathways. In this context, reprogramming the metabolism of effector and regulatory immune cells represents a promising therapeutic avenue. This review focuses on a relatively underexplored aspect of liver cancer immunology, the immunosuppressive role of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) driven by metabolic alterations and how these mechanisms contribute to the suppression of effective anti-tumor immune responses.
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Affiliation(s)
- Patrizio Caini
- Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
| | - Vinicio Carloni
- Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
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Gao B, Lu Y, Lai X, Xu X, Gou S, Yang Z, Gong Y, Yang H. Metabolic reprogramming in hepatocellular carcinoma: mechanisms of immune evasion and therapeutic implications. Front Immunol 2025; 16:1592837. [PMID: 40370433 PMCID: PMC12075234 DOI: 10.3389/fimmu.2025.1592837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Accepted: 04/07/2025] [Indexed: 05/16/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with limited treatment options for advanced stages. Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to the harsh tumor microenvironment (TME) and evade immune surveillance. This review involves the role of metabolic reprogramming in HCC, focusing on the dysregulation of glucose, lipid, and amino acid metabolism, and its impact on immune evasion. Key metabolic pathways, such as the Warburg effect, fatty acid synthesis, and glutaminolysis, are discussed, along with their influence on tumor-associated macrophages (TAMs) and immune cell function. Targeting these metabolic alterations presents a promising therapeutic approach to enhance immunotherapy efficacy and improve HCC patient outcomes.
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Affiliation(s)
- Bocheng Gao
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yan Lu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xingyue Lai
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xi Xu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shuhua Gou
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhida Yang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanju Gong
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hong Yang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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4
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Costantini S, Madonna G, Capone M, Di Gennaro E, Bagnara P, Renza F, Mallardo D, Affatato R, Vitagliano C, Romanelli M, Tuffanelli M, Simeone E, Ciliberto G, Ascierto PA, Budillon A. Metabolomic signatures in liquid biopsy are associated with overall survival in metastatic melanoma patients treated with immune checkpoint inhibitor therapy. J Exp Clin Cancer Res 2025; 44:119. [PMID: 40211360 PMCID: PMC11983745 DOI: 10.1186/s13046-025-03378-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 03/27/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs), such as anti-Cytotoxic T-Lymphocyte Antigen 4(CTLA-4) and anti-Programmed cell death protein 1 (PD-1) agents, have improved the prognosis of patients with metastatic melanoma. However, a proportion of patients develop resistance to these treatments, leading to a poor prognosis. Therefore, identifying potential non invasive and easy to measure biomarkers is crucial for guiding treatment strategies in patients with metastatic melanoma. METHODS A retrospective single-center study was conducted involving patients with metastatic stage IV melanoma who received first-line treatment with anti-CTL4 and/or anti-PD-1 agents. The patients were categorized into two groups on the basis of their 1-year overall survival (OS): those with good outcomes (long-term OS ≥ 1 year) and those with poor outcomes (short-term OS < 1 year). Peripheral metabolomics was performed using baseline sera from 132 patients via 600 MHz Nuclear Magnetic Resonance (NMR) spectroscopy. Enriched functional analysis was conducted to identify the metabolic pathways in which significant metabolites were involved. RESULTS Sparse partial least squares discriminant analysis (sPLS-DA) and loading plots obtained by analyzing the metabolomics profiles of samples collected before ICI treatment revealed significantly different levels of metabolites between the two groups (long-term OS vs. short-term OS). Specifically, lactate, tryptophan and valine significantly predicted the OS of the whole study population subjected to ICI immunotherapy; alanine, asparagine, glutathione, histidine, isoleucine and phenylalanine significantly predicted the OS of patients treated with ipilimumab; glucose, glutamine, histidine and proline significantly predicted the OS of patients treated with nivolumab; and lactate, lysine and proline significantly predicted the OS of patients treated with ipilimumab plus nivolumab. Notably, tryptophan levels were correlated with treatment response in the overall patient group, whereas histidine and lactate levels were associated with response in patients treated with ipilimumab and with ipilimumab plus nivolumab, respectively. Interestingly, higher pretreatment levels of histidine were commonly found in long-term OS subgroups of patients treated with ipilimumab, nivolumab or ipilimumab plus nivolumab. Interestingly, considering only those metabolites that predict OS after univariate analysis, higher histidine, and lower lactate and proline levels resulted as associated with favorable OS in at least two patient cohorts. CONCLUSIONS Overall, this exploratory liquid biopsy study revealed a strong correlation between the pretreatment levels of some metabolites and the OS of patients with metastatic stage IV melanoma treated with anti-CTL4 and/or anti-PD-1 antibodies in the first-line setting and revealed the potential of these molecules to predict outcomes and define personalized management and treatment strategies.
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Affiliation(s)
- Susan Costantini
- Experimental Pharmacology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Gabriele Madonna
- Cancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Mariaelena Capone
- Cancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Elena Di Gennaro
- Experimental Pharmacology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Palmina Bagnara
- Experimental Pharmacology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Federica Renza
- Experimental Pharmacology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Domenico Mallardo
- Cancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Roberta Affatato
- Experimental Pharmacology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Carlo Vitagliano
- Experimental Pharmacology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Marilena Romanelli
- Cancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Marilena Tuffanelli
- Cancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Ester Simeone
- Cancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | | | - Paolo A Ascierto
- Cancer Immunotherapy and Development Therapeutics Unit, Melanoma, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy
| | - Alfredo Budillon
- Scientific Directorate, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, 80131, Italy.
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Liu G, Hong T, Liu X, Lin X, Yao P, Chen X, Zhang Y, Sarica K, Hong X. Predictive role of lactylation-related gene signature in the prognosis and immunotherapy response in bladder cancer. Arch Ital Urol Androl 2025; 97:13516. [PMID: 39968644 DOI: 10.4081/aiua.2025.13516] [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: 12/22/2024] [Accepted: 01/13/2025] [Indexed: 02/20/2025] Open
Abstract
OBJECTIVE Lactylation is a type of chemical modification involving the introduction of lactyl groups to a molecule which can affect the interactions between tumor cells and their microenvironment. This study aims to evaluate the possible role of lactylation-related gene signature in the prediction of both prognosis and immunotherapy response in bladder cancer (BLCA). METHODS Lactylation-related genes were obtained from the published work and two subtypes (cluster A and B) were identified through unsupervised clustering. The differences including clinical features, differentially expressed genes (DEGs), pathways, and immune cell infiltration between these two clusters were thoroughly examined. RESULTS By utilizing the DEGs between the two clusters, a lactylation score was identified to predict the overall survival status and the response of BLCA patients receiving immunotherapy. Our results demonstrated that patients with a high lactylation score tended to have a worse survival period and increased immune cell infiltration level. Further analysis showed that high lactylation score may be associated with higher sensitivity to immune checkpoint inhibitor (ICI) treatment which is crucial in the identification of the suitable candidates for ICI therapy. CONCLUSIONS Our results emphasize the possible predictive role of lactylation-related gene signature both in the survival rates of BLCA and its implications for treatment strategies.
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Affiliation(s)
- Guoyuan Liu
- Department of Urology, Shantou Central Hospital, Shantou.
| | - Ting Hong
- Clinical Medical Research Center, Shantou Central Hospital, Shantou.
| | - Xinyu Liu
- Clinical Medical Research Center, Shantou Central Hospital, Shantou.
| | - Xuanhao Lin
- Department of Biobank, Shantou Central Hospital, Shantou.
| | - Peixiu Yao
- Department of Biobank, Shantou Central Hospital, Shantou.
| | - Xifeng Chen
- Department of Biobank, Shantou Central Hospital, Shantou.
| | - Yonghai Zhang
- Department of Urology, Health Sciences University, Prof. Dr. Ilhan Varank Education and Training Hospital, Istanbul; Department of Urology, Biruni University, Medical School, Istanbul.
| | - Kemal Sarica
- Department of Urology, Health Sciences University, Prof. Dr. Ilhan Varank Education and Training Hospital; Department of Urology, Biruni University, Medical School, Istanbul.
| | - Xuwei Hong
- Department of Urology, Shantou Central Hospital, Shantou.
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Wu Y, Xie BB, Zhang BL, Zhuang QX, Liu SW, Pan HM. Apatinib regulates the glycolysis of vascular endothelial cells through PI3K/AKT/PFKFB3 pathway in hepatocellular carcinoma. World J Gastroenterol 2025; 31:102848. [PMID: 40124275 PMCID: PMC11924011 DOI: 10.3748/wjg.v31.i11.102848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/17/2025] [Accepted: 02/11/2025] [Indexed: 03/13/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy in the Chinese population; the severe vascularization by the tumor makes it difficult to cure. The high incidence and poor survival rates of this disease indicate the search for new therapeutic alternatives. Apatinib became a drug of choice because it inhibits tyrosine kinase activity, mainly through an effect on vascular endothelial growth factor receptor-2, thereby preventing tumor angiogenesis. This mechanism of action makes apatinib effective in the treatment of HCC. AIM To investigate the effect of apatinib on the glycolysis of vascular endothelial cells (VECs). METHODS This present study has investigated the effects of HCC cells on VECs, paying particular attention to changes in the glycolytic activity of VECs. The co-culture system established in the present study examined key cellular functions such as extracellular acidification rate and oxygen consumption rate. It also discusses participation of apatinib in the above processes. Core to the findings is the phosphatidylinositol 3-kinase (PI3K)/AKT/6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling pathway, emphasizing the function of phosphorylated AKT and its interaction with PFKFB3, an essential regulator of glycolysis. In the investigation, molecular mechanisms by which such a pathway could influence the above VECs functions of proliferation, migration, and tube formation were underlined through coimmunoprecipitation analysis. Besides, supplementary in vivo experiments on nude mice provided additional biological relevance to the obtained results. RESULTS The glycolytic metabolism in VECs co-cultured with HCC cells is highly active, and the increased glycolysis in these endothelial cells accelerates the malignant transformation of HCC cells. Apatinib has been shown to inhibit this glycolytic activity in the VECs. It also hinders the development, multiplication, and movement of these cells while encouraging their programmed cell death. Moreover, biological analysis revealed that apatinib mainly influences VECs by regulating the PI3K/AKT signaling pathway. Subsequent research indicated that apatinib blocks the PI3K/AKT/PFKEB3 pathway, which in turn reduces glycolysis in these cells. CONCLUSION Apatinib influences the glycolytic pathway in the VECs of HCC a through the PI3K/AKT/PFKFB3 signaling pathway.
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Affiliation(s)
- Yi Wu
- Division of Cancer Medicine, Sir Run Run Shaw Medical Center, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Bin-Bin Xie
- Division of Cancer Medicine, Sir Run Run Shaw Medical Center, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Bing-Liang Zhang
- Section of Oncology, Ningxia Hui Autonomous Region General Hospital, Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
| | - Qing-Xin Zhuang
- Section of Oncology, Ningxia Hui Autonomous Region General Hospital, Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
| | - Shi-Wei Liu
- Section of Oncology, Ningxia Hui Autonomous Region General Hospital, Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
| | - Hong-Ming Pan
- Division of Cancer Medicine, Sir Run Run Shaw Medical Center, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
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Yoo SK, Kim JH, Choe WH, Kwon SY. Comparison of Mortality Prediction Between the Model for End-Stage Liver Disease-3.0 (MELD-3.0) and the Model for End-Stage Liver Disease-Lactate (MELD-La) in Korean Patients with Liver Cirrhosis. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:494. [PMID: 40142305 PMCID: PMC11943487 DOI: 10.3390/medicina61030494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/07/2025] [Accepted: 03/11/2025] [Indexed: 03/28/2025]
Abstract
Background and Objectives: The Model for End-Stage Liver Disease (MELD) score has widely been used for mortality prediction in liver cirrhosis (LC) patients and transplantation allocation. There have been recent modifications of MELD scores, such as MELD-Lactate (MELD-La) and MELD-3.0. The goal of this study was to compare MELD, MELD-La, and MELD-3.0 in predicting mortality among LC patients in Korea. Materials and Methods: This is a retrospective, single-centered study in which LC patients admitted to Konkuk University Hospital between January 2011 and December 2022 were enrolled and reviewed. Predictive values for 1- and 3-month mortality for MELD, MELD-La, and MELD-3.0 were calculated using the area under the receiver operating characteristic (AUROC) curve. Differences between AUROCs were statistically analyzed using DeLong's test. Results: A total of 1152 patients were initially included in this study. Among them, 165 (14.3%) patients died within one month, and 211 (19.7%) died within three months. The AUROCs for 1-month mortality of MELD, MELD-La, and MELD-3.0 were 0.808, 0.79, and 0.807, respectively. For the 3-month mortality of MELD, MELD-La, and MELD-3.0, the AUROCs were 0.805, 0.753, and 0.817, respectively. Multiple comparisons of ROC curves demonstrated that MELD and MELD-3.0 reflected the 3-month mortality prediction of LC patients better than MELD-La (p = 0.0018, p = 0.0003, respectively). Conclusions: This study demonstrated that MELD and MELD-3.0 outperformed MELD-La in predicting the 3-month mortality for LC patients. However, there was no significant difference between MELD and MELD-3.0 in predicting LC patient mortality.
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Affiliation(s)
- Seung-Kang Yoo
- Department of Internal Medicine, Konkuk University Medical Center, Seoul 05030, Republic of Korea; (S.-K.Y.); (W.-H.C.); (S.-Y.K.)
| | - Jeong-Han Kim
- Department of Internal Medicine, Konkuk University Medical Center, Seoul 05030, Republic of Korea; (S.-K.Y.); (W.-H.C.); (S.-Y.K.)
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul 05029, Republic of Korea
| | - Won-Hyeok Choe
- Department of Internal Medicine, Konkuk University Medical Center, Seoul 05030, Republic of Korea; (S.-K.Y.); (W.-H.C.); (S.-Y.K.)
| | - So-Young Kwon
- Department of Internal Medicine, Konkuk University Medical Center, Seoul 05030, Republic of Korea; (S.-K.Y.); (W.-H.C.); (S.-Y.K.)
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Luo Y, Zhang N, Ye J, Wang Z, Zhou X, Liu J, Cai J, Li C, Chen L. Unveiling lactylation modification: A new hope for cancer treatment. Biomed Pharmacother 2025; 184:117934. [PMID: 39986235 DOI: 10.1016/j.biopha.2025.117934] [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: 12/29/2024] [Revised: 02/13/2025] [Accepted: 02/18/2025] [Indexed: 02/24/2025] Open
Abstract
This review article delves into the multifaceted role of lactylation modification in antitumor therapy, revealing the complex interplay between lactylation modification and the tumor microenvironment (TME), metabolic reprogramming, gene expression, and immunotherapy. As an emerging epigenetic modification, lactylation has a significant impact on the metabolic pathways of tumor cells, immune evasion, gene expression regulation, and sensitivity to chemotherapy drugs. Studies have shown that lactylation modification significantly alters the development and therapeutic response of tumors by affecting metabolites in the TME, immune cell functions, and signaling pathways. In the field of immunotherapy, the regulatory role of lactylation modification provides a new perspective and potential targets for tumor treatment, including modulating the sensitivity of tumors to immunotherapy by affecting the expression of immune checkpoint molecules and the infiltration of immune cells. Moreover, research progress on lactylation modification in various types of tumors indicates that it may serve as a biomarker to predict patients' responses to chemotherapy and immunotherapy. Overall, research on lactylation modification provides a theoretical foundation for the development of new tumor treatment strategies and holds promise for improving patient prognosis and quality of life. Future research will further explore the application potential of lactylation modification in tumor therapy and how to improve treatment efficacy by targeting lactylation modification.
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Affiliation(s)
- Yuxiang Luo
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Ning Zhang
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jiarong Ye
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Zuao Wang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Xinchi Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jipeng Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jing Cai
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Chen Li
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China; Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Disease, Jiangxi 330006, China; Institute of Minimally Invasive Orthopedics, Nanchang University, Jiangxi 330006, China.
| | - Leifeng Chen
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Precision Oncology Medicine Center,The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People's Republic of China.
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Yu L, Shi Y, Zhi Z, Li S, Yu W, Zhang Y. Establishment of a Lactylation-Related Gene Signature for Hepatocellular Carcinoma Applying Bulk and Single-Cell RNA Sequencing Analysis. Int J Genomics 2025; 2025:3547543. [PMID: 39990773 PMCID: PMC11845269 DOI: 10.1155/ijog/3547543] [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: 10/16/2024] [Accepted: 01/08/2025] [Indexed: 02/25/2025] Open
Abstract
Background: Lactylation is closely involved in cancer progression, but its role in hepatocellular carcinoma (HCC) is unclear. The present work set out to develop a lactylation-related gene (LRG) signature for HCC. Methods: The lactylation score of tumor and normal groups was calculated using the gene set variation analysis (GSVA) package. The single-cell RNA sequencing (scRNA-seq) analysis of HCC was performed in the "Seurat" package. Prognostic LRGs were selected by performing univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses to develop and validate a Riskscore model. Functional enrichment analysis was conducted by gene set enrichment analysis (GSEA) using the "clusterProfiler" package. Genomic characteristics between different risk groups were compared, and tumor mutational burden (TMB) was calculated by the "Maftools" package. Immune cell infiltration was assessed by algorithms of cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT), microenvironment cell populations-counter (MCP-counter), estimating the proportions of immune and cancer cells (EPIC), tumor immune estimation resource (TIMER), and single-sample gene set enrichment analysis (ssGSEA). Immunotherapy response was predicted by the tumor immune dysfunction and exclusion (TIDE) algorithm. Drug sensitivity was analyzed using the "pRRophetic" package. A nomogram was established using the "rms" package. The expressions of the prognostic LRGs in HCC cells were verified by in vitro test, and cell counting kit-8 (CCK-8), wound healing, and transwell assays were carried out to measure the viability, migration, and invasion of HCC cells. Results: The lactylation score, which was higher in the tumor group than in the normal group, has been confirmed as an independent factor for the prognostic evaluation in HCC. Six prognostic LRGs, including two protective genes (FTCD and APCS) and four risk genes (LGALS3, C1orf43, TALDO1, and CCT5), were identified to develop a Riskscore model with a strong prognostic prediction performance in HCC. The scRNA-seq analysis revealed that LGALS3 was largely expressed in myeloid cells, while APCS, FTCD, TALDO1, CCT5, and C1orf43 were mainly expressed in hepatocytes. The high-risk group was primarily enriched in the pathways involved in tumor occurrence and development, with higher T cell infiltration. Moreover, the high-risk group was found to be less responsive to immunotherapy but was more sensitive to chemotherapeutic drugs. By integrating Riskscore and clinical features, a nomogram with a high predictive accuracy was developed. Additionally, C1orf43, CCT5, TALDO1, and LGALS3 were highly expressed in HCC cells. Silencing CCT5 inhibited the viability, migration, and invasion of HCC cells. Conclusion: The present work developed a novel LRG gene signature that could be considered a promising therapeutic target and biomarker for HCC.
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Affiliation(s)
- Lianghe Yu
- Hepatobiliary Surgery, The Third Affiliated Hospital, Naval Military Medical University, Shanghai, China
| | - Yan Shi
- Hepatobiliary Surgery, The Third Affiliated Hospital, Naval Military Medical University, Shanghai, China
| | - Zhenyu Zhi
- Hepatobiliary Surgery, The Third Affiliated Hospital, Naval Military Medical University, Shanghai, China
| | - Shuang Li
- Bioinformatics R&D Department, Hangzhou Mugu Technology Co., Ltd, Hangzhou, China
| | - Wenlong Yu
- Hepatobiliary Surgery, The Third Affiliated Hospital, Naval Military Medical University, Shanghai, China
| | - Yongjie Zhang
- Hepatobiliary Surgery, The Third Affiliated Hospital, Naval Military Medical University, Shanghai, China
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10
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Yu D, Zhong Q, Wang Y, Yin C, Bai M, Zhu J, Chen J, Li H, Hong W. Lactylation: The metabolic accomplice shaping cancer's response to radiotherapy and immunotherapy. Ageing Res Rev 2025; 104:102670. [PMID: 39864560 DOI: 10.1016/j.arr.2025.102670] [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: 11/19/2024] [Revised: 01/09/2025] [Accepted: 01/22/2025] [Indexed: 01/28/2025]
Abstract
Protein lactylation, an emerging post-translational modification, is providing new insights into tumor biology and challenging our current understanding of cancer mechanisms. Our review illuminates the intricate roles of lactylation in carcinogenesis, tumor progression, and therapeutic responses, positioning it as a critical linchpin connecting metabolic reprogramming, epigenetic modulation, and treatment outcomes. We provide an in-depth analysis of lactylation's molecular mechanisms and its far-reaching impact on cell cycle regulation, immune evasion strategies, and therapeutic resistance within the complex tumor microenvironment. Notably, this review dissects the paradoxical nature of lactylation in cancer immunotherapy and radiotherapy. While heightened lactylation can foster immune suppression and radioresistance, strategically targeting lactylation cascades opens innovative avenues for amplifying the efficacy of current treatment paradigms. We critically evaluate lactylation's potential as a robust diagnostic and prognostic biomarker and explore frontier therapeutic approaches targeting lactylation. The synergistic integration of multi-omics data and artificial intelligence in lactylation research is catalyzing significant strides towards personalized cancer management. This review not only consolidates current knowledge but also charts a course for future investigations. Key research imperatives include deciphering tumor-specific lactylation signatures, optimizing synergistic strategies combining lactylation modulation with immune checkpoint inhibitors and radiotherapy, and comprehensively assessing the long-term physiological implications of lactylation intervention. As our understanding of lactylation's pivotal role in tumor biology continues to evolve, this burgeoning field promises to usher in transformative advancements in cancer diagnosis, treatment modalitie.
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Affiliation(s)
- Danqing Yu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Qingping Zhong
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Yanlin Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310000, China
| | - Chang Yin
- Nursing Department, Shanghai Sixth People's Hospital, Shanghai 200233, China
| | - Minghua Bai
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Ji Zhu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Jinggang Chen
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
| | - Huaming Li
- Department of Gastroenterology, Hangzhou Third Peoples Hospital, Hangzhou 310000, China.
| | - Weifeng Hong
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
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11
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Tang Z, Wei C, Deng X, Lin Q, Hu Q, Li S, Wang J, Wu Y, Liu D, Fang M, Zhan T. Serum proteomic and metabolomic profiling of hepatocellular carcinoma patients co-infected with Clonorchis sinensis. Front Immunol 2025; 15:1489077. [PMID: 39840062 PMCID: PMC11746118 DOI: 10.3389/fimmu.2024.1489077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Accepted: 12/10/2024] [Indexed: 01/23/2025] Open
Abstract
Background Clonorchis sinensis (C. sinensis) infection is a significant risk factor for hepatocellular carcinoma (HCC), yet its underlying mechanisms remain poorly understood. This study aimed to investigate the impact of C. sinensis infection on the serum proteomic and metabolomic profiling of HCC patients, focusing on the potential mechanisms. Method A retrospective clinical analysis was conducted on 1121 HCC patients, comparing those with and without C. sinensis infection. The influence of C. sinensis on serum proteome and metabolome in HCC was further assessed. Result C. sinensis infection correlated with a younger age at cancer onset, male predominance, advanced cancer stage, liver cirrhosis, and microvascular invasion in HCC patients. It also associated with shorter overall survival (OS) and recurrence-free survival (RFS). The levels of blood lipids (e.g., APO-A, HDL-C, and TG) were significantly altered after C. sinensis infection. Proteomic and metabolomic analyses revealed metabolic reprogramming caused by C. sinensis, with excessive depletion of argininosuccinate synthase (ASS) and D-glucose as potential factors in C. sinensis-associated HCC malignancy. Key molecules ILF2, CNN2, OLFM4, NOTCH3, and LysoPA were implicated in HCC progression. Furthermore, C. sinensis triggered inflammation, insulin resistance, and pro-tumor immune escape, and exacerbated the complication of degenerative diseases. Conclusion This study not only provides compelling evidence for elucidating the mechanisms underlying C. sinensis-mediated HCC development but also identifies potential therapeutic targets for HCC patients co-infected with C. sinensis.
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Affiliation(s)
- Zeli Tang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
- Key Laboratory of Basic Research on Regional Diseases, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, China
| | - Caibiao Wei
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xueling Deng
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Qiumei Lin
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Qiping Hu
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
- Key Laboratory of Basic Research on Regional Diseases, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, China
| | - Shitao Li
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Jilong Wang
- Department of Parasitology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Yuhong Wu
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Dengyu Liu
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
- Key Laboratory of Basic Research on Regional Diseases, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, China
- Department of Parasitology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Min Fang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
- Engineering Research Center for Tissue & Organ Injury and Repair Medicine, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Tingzheng Zhan
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
- Key Laboratory of Basic Research on Regional Diseases, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, China
- Department of Parasitology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
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12
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Xu ZP, Shan SY, Cai EW, Wu YY. Gegen Qinlian decoction inhibited M1 macrophage polarization and ulcerative colitis progression through regulating histone lactylation. Tissue Cell 2024; 89:102468. [PMID: 39003913 DOI: 10.1016/j.tice.2024.102468] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 06/26/2024] [Accepted: 07/08/2024] [Indexed: 07/16/2024]
Abstract
Ulcerative colitis (UC) is a persistent inflammatory condition affecting the bowels. Gegen Qinlian decoction (GQD) has been widely used in the therapy of gastrointestinal diseases. We investigated the protective impacts and mechanism of GQD against UC. To establish the UC model, dextran sulfate sodium (DSS) was utilized. The disease activity index (DAI), colon length and colonic pathology were assessed to examine the impacts of GQD on UC. The level of pan-lysine lactylation (Pan kla) and specific sites were detected using western blot. Then, the inflammatory factors and the oxidative stress parameters were measured via the corresponding kits, respectively. Our findings demonstrated that GQD suppressed the lactate generation and LDH activity. The western blot revealed that GQD inhibited the expression of Pan kla and specific sites of H3K18la, H3K23la, H4K8la, and H4K12la. Furthermore, the suppressive effects on inflammation and oxidative stress caused by GQD were counteracted upon the exogenous lactate. GQD suppressed the phenotypic differentiation of M1 macrophages by reducing the expression of M1 markers, which was also reversed by exogenous lactate. In conclusion, GQD effectively suppressed UC progression through histone lactylation. Our results broadened the theoretical basis for the clinical use of GQD.
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Affiliation(s)
- Zhen-Peng Xu
- Department of Colorectal Surgery, People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China; Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Su-Yuan Shan
- Department of Colorectal Surgery, People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China
| | - Er-Wei Cai
- Department of Colorectal Surgery, People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China.
| | - Yan-Yan Wu
- Department of Colorectal Surgery, People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China.
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13
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Wang G, Zou X, Chen Q, Nong W, Miao W, Luo H, Qu S. The relationship and clinical significance of lactylation modification in digestive system tumors. Cancer Cell Int 2024; 24:246. [PMID: 39010066 PMCID: PMC11251390 DOI: 10.1186/s12935-024-03429-8] [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: 02/27/2024] [Accepted: 07/02/2024] [Indexed: 07/17/2024] Open
Abstract
Lactylation, an emerging post-translational modification, plays a pivotal role in the initiation and progression of digestive system tumors. This study presents a comprehensive review of lactylation in digestive system tumors, underscoring its critical involvement in tumor development and progression. By focusing on metabolic reprogramming, modulation of the tumor microenvironment, and the molecular mechanisms regulating tumor progression, the potential of targeting lactylation as a therapeutic strategy is highlighted. The research reveals that lactylation participates in gene expression regulation and cell signaling by affecting the post-translational states of histones and non-histone proteins, thereby influencing metabolic pathways and immune evasion mechanisms in tumor cells. Furthermore, this study assesses the feasibility of lactylation as a therapeutic target, providing insights for clinical treatment of gastrointestinal cancers. Future research should concentrate on elucidating the mechanisms of lactylation, developing efficient lactylation inhibitors, and validating their therapeutic efficacy in clinical trials, which could transform current cancer treatment and immunotherapy approaches. In summary, this review emphasizes the crucial role of lactylation in tumorigenesis and progression through a detailed analysis of its molecular mechanisms and clinical significance.
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Affiliation(s)
- Gang Wang
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Xiaosu Zou
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Qicong Chen
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Wenqian Nong
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Weiwei Miao
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Honglin Luo
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China.
| | - Shenhong Qu
- Institute of Oncology, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China.
- Department of Otolaryngology & Head and Neck, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, Guangxi, China.
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14
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Yao S, Chai H, Tao T, Zhang L, Yang X, Li X, Yi Z, Wang Y, An J, Wen G, Jin H, Tuo B. Role of lactate and lactate metabolism in liver diseases (Review). Int J Mol Med 2024; 54:59. [PMID: 38785162 PMCID: PMC11188982 DOI: 10.3892/ijmm.2024.5383] [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: 01/31/2024] [Accepted: 03/22/2024] [Indexed: 05/25/2024] Open
Abstract
Lactate is a byproduct of glycolysis, and before the Warburg effect was revealed (in which glucose can be fermented in the presence of oxygen to produce lactate) it was considered a metabolic waste product. At present, lactate is not only recognized as a metabolic substrate that provides energy, but also as a signaling molecule that regulates cellular functions under pathophysiological conditions. Lactylation, a post‑translational modification, is involved in the development of various diseases, including inflammation and tumors. Liver disease is a major health challenge worldwide. In normal liver, there is a net lactate uptake caused by gluconeogenesis, exhibiting a higher net lactate clearance rate compared with any other organ. Therefore, abnormalities of lactate and lactate metabolism lead to the development of liver disease, and lactate and lactate metabolism‑related genes can be used for predicting the prognosis of liver disease. Targeting lactate production, regulating lactate transport and modulating lactylation may be potential treatment approaches for liver disease. However, currently there is not a systematic review that summarizes the role of lactate and lactate metabolism in liver diseases. In the present review, the role of lactate and lactate metabolism in liver diseases including liver fibrosis, non‑alcoholic fatty liver disease, acute liver failure and hepatocellular carcinoma was summarized with the aim to provide insights for future research.
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Affiliation(s)
- Shun Yao
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Hongyu Chai
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Ting Tao
- Department of Burns and Plastic Surgery, Fuling Hospital, Chongqing University, Chongqing 408099, P.R. China
| | - Li Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Xingyue Yang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Xin Li
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Zhiqiang Yi
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Yongfeng Wang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Jiaxin An
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Guorong Wen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Hai Jin
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
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15
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Yue B, Gao Y, Hu Y, Zhan M, Wu Y, Lu L. Harnessing CD8 + T cell dynamics in hepatitis B virus-associated liver diseases: Insights, therapies and future directions. Clin Transl Med 2024; 14:e1731. [PMID: 38935536 PMCID: PMC11210506 DOI: 10.1002/ctm2.1731] [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: 02/05/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/29/2024] Open
Abstract
Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8+ T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8+ T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8+ T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8+ T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8+ T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8+ T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8+ T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.
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Affiliation(s)
- Bing Yue
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yuxia Gao
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yi Hu
- Microbiology and Immunology DepartmentSchool of MedicineFaculty of Medical ScienceJinan UniversityGuangzhouGuangdongChina
| | - Meixiao Zhan
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yangzhe Wu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
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16
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Hu N, Li H, Tao C, Xiao T, Rong W. The Role of Metabolic Reprogramming in the Tumor Immune Microenvironment: Mechanisms and Opportunities for Immunotherapy in Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:5584. [PMID: 38891772 PMCID: PMC11171976 DOI: 10.3390/ijms25115584] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/16/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
As one of the emerging hallmarks of tumorigenesis and tumor progression, metabolic remodeling is common in the tumor microenvironment. Hepatocellular carcinoma (HCC) is the third leading cause of global tumor-related mortality, causing a series of metabolic alterations in response to nutrient availability and consumption to fulfill the demands of biosynthesis and carcinogenesis. Despite the efficacy of immunotherapy in treating HCC, the response rate remains unsatisfactory. Recently, research has focused on metabolic reprogramming and its effects on the immune state of the tumor microenvironment, and immune response rate. In this review, we delineate the metabolic reprogramming observed in HCC and its influence on the tumor immune microenvironment. We discuss strategies aimed at enhancing response rates and overcoming immune resistance through metabolic interventions, focusing on targeting glucose, lipid, or amino acid metabolism, as well as systemic regulation.
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Affiliation(s)
- Nan Hu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
| | - Haiyang Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
| | - Changcheng Tao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
| | - Ting Xiao
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Weiqi Rong
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
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17
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Qiu X, Dong L, Wang K, Zhong X, Xu H, Xu S, Guo H, Wei X, Chen W, Xu X. Development and Validation of a Novel Nomogram Integrated with Hypoxic and Lactate Metabolic Characteristics for Prognosis Prediction in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2024; 11:241-255. [PMID: 38333220 PMCID: PMC10850990 DOI: 10.2147/jhc.s446313] [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: 11/06/2023] [Accepted: 01/24/2024] [Indexed: 02/10/2024] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Accumulating evidence indicates that hypoxia and lactate metabolism play critical roles in tumor progression and therapeutic efficacy. This study aimed to construct a hypoxia- and lactate metabolism-related prognostic model (HLPM) to evaluate survival and treatment responses for HCC patients and develop a nomogram integrated with HLPM and clinical characteristics for prognosis prediction in HCC. Methods Expression profile and clinical data of HCC were obtained from TCGA and ICGC databases. The univariate, LASSO and stepwise multivariate Cox analyses were used to identify the hypoxia- and lactate metabolism-related biomarkers, whose expression levels were then validated in 14 pairs tissue samples and single-cell RNA sequencing dataset. Kaplan-Meier survival curves were utilized to assess the prognostic values of biomarkers or models. Analyses of ImmuCellAI, TIDE and drug sensitivity were conducted to evaluate the therapeutic responses of patients. Furthermore, the nomogram integrated with hypoxic and lactate metabolic characteristics was established through univariate and multivariate Cox analyses. ROC curves, C-index, and calibration curves were depicted to evaluate the performance of the nomogram. Results Five hypoxia- and lactate metabolism-related biomarkers (KIF20A, IRAK1, ADM, PPARGC1A and EPO) were used to construct HLPM. The expression of five prognostic biomarkers was validated in 14 pairs tissue samples and single-cell RNA sequencing dataset. Analyses of ImmuCellAI, TIDE and drug sensitivity implied that patients with low-risk score were more sensitive to immunotherapy and major chemotherapeutic agents. The nomogram that contained age, histological grade and risk score of HLPM was developed and exhibited a better capacity in prognosis prediction than HLPM only. Conclusion A novel nomogram integrated with hypoxic and lactate metabolic characteristics was developed and validated for prognosis prediction in HCC, providing insight into personalized decision-making in clinical management.
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Affiliation(s)
- Xun Qiu
- Department of Surgery, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Libin Dong
- Department of Surgery, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Kai Wang
- Department of Surgery, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Xinyang Zhong
- Department of Surgery, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Hanzhi Xu
- Department of Surgery, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Shengjun Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Haijun Guo
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Xuyong Wei
- Department of Surgery, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Wei Chen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, 310058, People's Republic of China
| | - Xiao Xu
- Department of Surgery, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
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18
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Zhang J, Dong K, Zhang X, Li C, Yu J, Wang W. Characteristics of lactate metabolism phenotype in hepatocellular carcinoma. Sci Rep 2023; 13:19674. [PMID: 37952028 PMCID: PMC10640573 DOI: 10.1038/s41598-023-47065-0] [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: 07/13/2023] [Accepted: 11/08/2023] [Indexed: 11/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, and more effective prognostic markers are needed. Lactic acid has been proved to be an important metabolite involved in cancer development, metastasis, and the tumor microenvironment, affecting the prognosis of patients. The role of lactic acid metabolism regulators (LAMRs) in HCC is still unclear. In this study, we analyzed the status of LAMRs, a gene list containing lactate from Molecular Signatures database, in HCC and consensus clustering was performed based on these LAMRs. Cluster B showed higher infiltrations of immune cells, higher TME scores, and a poorer prognosis. We further constructed a risk score based on DEGs using LASSO and COX regression analysis between two clusters, which could effectively predict the prognosis of TCGA-LIHC patients. The GSE14520 cohort confirmed the result. We also examined the correlation of risk scores with clinical characteristics, genetic mutations, drug sensitivity, immune checkpoint inhibitors(ICIs), and immunotherapy. In conclusion, our findings will facilitate a further understanding of the role of partial lactate metabolism related genes in HCC and suggest a new risk score to predict prognosis.
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Affiliation(s)
- Jiacheng Zhang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Keshuai Dong
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Xin Zhang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Chunlei Li
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Jia Yu
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China.
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, People's Republic of China.
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19
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Adugna A. Histomolecular characterisation of hepatitis B virus induced liver cancer. Rev Med Virol 2023; 33:e2485. [PMID: 37902197 DOI: 10.1002/rmv.2485] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 08/06/2023] [Accepted: 09/26/2023] [Indexed: 10/31/2023]
Abstract
Hepatitis B virus (HBV)-associated liver cancer is the third most prevalent cancer-related cause of death worldwide. Different studies have been done on the histomolecular analysis of HBV induced-liver cancer including epigenetics which are dynamic molecular mechanisms to control gene expression without altering the host deoxyribonucleic acid, genomics characterise the integration of the viral genome with host genome, proteomics characterise how gene modifies and results overexpression of proteins, glycoproteomics discover different glyco-biomarker candidates and show glycosylation in malignant hepatocytes, metabolomics characterise how HBV impairs a variety of metabolic functions during hepatocyte immortalisation, exosomes characterise immortalised liver cells in terms of their differentiation and proliferation, and autophagy plays a role in the development of hepatocarcinogenesis linked to HBV infection.
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Affiliation(s)
- Adane Adugna
- Medical Microbiology, Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
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El Sayed SM. Al-Hijamah (Prophetic Wet Cupping Therapy) is a Novel Adjuvant Treatment for Viral Hepatitis That Excretes Viral Particles and Excess Ferritin Percutaneously, Synergizes Pharmacotherapy, Enhances Antiviral Immunity and Helps Better HCC Prevention and Treatment: A Novel Evidence-Based Combination with Prophetic Medicine Remedies. J Hepatocell Carcinoma 2023; 10:1527-1546. [PMID: 37727876 PMCID: PMC10505647 DOI: 10.2147/jhc.s409526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 08/12/2023] [Indexed: 09/21/2023] Open
Abstract
Viral hepatitis progresses to liver cirrhosis and HCC. Several challenges are facing Sovaldi treatment to viral C hepatitis, eg, viral resistance, difficulty to treat all genotypes, and inability to access treatments in low-income countries. Also, current treatments to Hepatitis B are still challenging. Ideal treatments to viral hepatitis should decrease the viral load, enhance antiviral immunity and repair the viruses-induced tissue damage. That is still beyond reach. High serum ferritin in viral hepatitis correlates with chronicity, increased necro-inflammation, hepatotoxicity, progression to cirrhosis, progression to HCC, unresponsiveness to treatments and viremia. Previously, Al-hijamah (wet cupping therapy of prophetic medicine) significantly cleared thalassemic children of causative pathological substances (CPS), eg, excess ferritin, free radicals and serum lipids. Moreover, Al-hijamah significantly increased the antioxidant power and potentiated the natural antiviral immunity, eg, increasing CD4 count, CD8 count and CD4/CD8 ratio. Prophet Muhammad peace be upon him said: "If there is a benenvolence (benefit) in any of your medicines, benefit will be in shrtat mihjam (Al-hijamah), honey drink, and a stinge of fire compatible with disease and I do not like to cauterize". Likewise, the author suggests Al-hijamah as a novel promising adjuvant treatment for viral hepatitis (B and C) for percutaneous excretion of CPS as hepatitis viral particles, excess ferritin, inflammatory mediators, free radicals, and antigen-antibody complexes. Published reports proved that Al-hijamah exerted tissue-protective effects, and cleared blood through the fenestrated skin capillaries in a pressure-dependent and size-dependent manner (a kidney-like manner). That collectively may decrease the viral load for better HCC prevention and supports the evidence-based Taibah theory (Taibah mechanism). Same therapeutic benefits apply to other viral illnesses as AIDS. Even after HCC development, Al-hijamah is quite mandatory for excretion and clearance of CPS that favor malignancy, eg, lactate (Warburg effect), growth factors, metalloproteinases, and others. Al-hijamah-induced immune potentiation benefits HCC patients. Combining Al-hijamah with other natural antioxidant remedies of prophetic medicine, eg, nigella sativa, costus, natural honey, Zamzam water and others will maximize the therapeutic benefits. In conclusion, Al-hijamah and other prophetic medicine remedies are recommended adjuvants to current pharmacological treatments to viral hepatitis and HCC.
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Affiliation(s)
- Salah Mohamed El Sayed
- Al-Hijamah Clinic, Medical University Center, College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia
- Department of Clinical Biochemistry & Molecular Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia
- Department of Medical Biochemistry, Faculty of Medicine, Sohag University, Sohag, Egypt
- Prophetic Medicine Course & Research, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia
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PCSK9 Inhibitors in Cancer Patients Treated with Immune-Checkpoint Inhibitors to Reduce Cardiovascular Events: New Frontiers in Cardioncology. Cancers (Basel) 2023; 15:cancers15051397. [PMID: 36900189 PMCID: PMC10000232 DOI: 10.3390/cancers15051397] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/17/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
Cancer patients treated with immune checkpoint inhibitors (ICIs) are exposed to a high risk of atherosclerosis and cardiometabolic diseases due to systemic inflammatory conditions and immune-related atheroma destabilization. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein involved in metabolism of low-density lipoprotein (LDL) cholesterol. PCSK9 blocking agents are clinically available and involve monoclonal antibodies, and SiRNA reduces LDL levels in high-risk patients and atherosclerotic cardiovascular disease events in multiple patient cohorts. Moreover, PCSK9 induces peripheral immune tolerance (inhibition of cancer cell- immune recognition), reduces cardiac mitochondrial metabolism, and enhances cancer cell survival. The present review summarizes the potential benefits of PCSK9 inhibition through selective blocking antibodies and siRNA in patients with cancer, especially in those treated with ICIs therapies, in order to reduce atherosclerotic cardiovascular events and potentially improve ICIs-related anticancer functions.
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