Ferroptosis is an emerging form of programmed cell death triggered by iron-dependent lipid peroxidation. It is distinguished from other forms of cell death by its unique morphological changes and characteristic fine-tuned regulatory gene network. Since its pivotal involvement in the pathogenesis and therapeutic interventions of various diseases, such as malignant tumors, cardiovascular and cerebrovascular diseases, and traumatic disorders, has been well-established, ferroptosis has garnered significant attention in contemporary physiological and pathological research. For the advantage of alleviating the clinical symptoms and improving life quality, traditional Chinese medicine (TCM) holds a significant position in the treatment of these ailments. Moreover, increasing studies revealed that TCM compounds and monomers showed evident therapeutic efficacy by regulating ferroptosis via signaling pathways that tightly regulate redox reactions, iron ion homeostasis, lipid peroxidation, and glutathione metabolism. In this paper, we summarized the current knowledge of TCM compounds and monomers in regulating ferroptosis, aiming to provide a comprehensive review of disease management by TCM decoction, Chinese patent medicine, and natural products deriving from TCM through ferroptosis modulation. The formulation composition, chemical structure, and possible targets or mechanisms presented here offer valuable insights into the advancement of TCM exploration.

Oral squamous cell carcinoma (OSCC) is the predominant type of oral cancer, with over 370,000 new cases and approximately 170,000 deaths annually worldwide. Despite therapeutic advancements, OSCC mortality rates have been increasing, underscoring the need for improved prognostic models and therapeutic targets.

We integrated transcriptomic and clinical survival data from the TCGA-OSCC dataset to identify ferroptosis-related prognostic genes. Using weighted gene co-expression network analysis (WGCNA), we selected genes associated with OSCC prognosis and applied Lasso regression analysis to pinpoint key genes. A prognostic model was constructed and validated through survival analysis and receiver operating characteristic (ROC) curve analysis.

WGCNA identified modules significantly correlated with ferroptosis, yielding 321 genes associated with OSCC prognosis. Univariate Cox analysis identified 13 genes affecting OSCC prognosis. Lasso regression and multivariate Cox regression narrowed down the gene set to a final set of 7 genes, which were used to construct the risk model. The model stratified patients into high- and low-risk groups with significant survival differences (P < 0.001). The model's predictive accuracy was validated, with AUC values ranging from 0.565 to 0.733 for 1-, 3-, and 5-year survival predictions. Immune-related analysis revealed that low-risk patients exhibited higher immune cell infiltration and were more likely to benefit from immunotherapy.

Our study presents a novel prognostic model for OSCC patients based on ferroptosis-related genes, which not only predicts survival but also identifies potential therapeutic targets. The model's predictive accuracy and clinical relevance were validated, offering a new strategy for OSCC treatment.

The activation of ferroptosis in refractory cancers may enhances their sensitivity to apoptosis-based chemotherapy, resulting in a synergistic effect via combination therapy. To enhance the anticancer effect of JQ1, a known BRD4 inhibitor with a significant antiproliferative effect on triple-negative breast cancer (TNBC), various new JQ1 derivatives as dual ferroptosis and apoptosis inducers were designed and synthesized. Among them, compound BG11 revealed a remarkable inhibitory activity against TNBC cells and obviously suppressed BRD4 and GPX4 expression and activities. Further studies suggested that BG11 induced cell ferroptosis through promoting Fe2+ and intracellular lipid peroxide deposition. In addition, BG11 could induce apoptosis through increasing Bax (apoptotic protein) expression and decreasing Bcl-2 (anti-apoptotic protein) expression within MDA-MB-231 cells. Surprisingly, BG11 significantly inhibited tumor proliferation in the MDA-MB-231 xenograft model without obvious toxicity. Based on the above findings, BG11 may be the candidate dual ferroptosis and apoptosis inducers for treating TNBC.

The occurrence of necrosis during Mycobacterium bovis (M. bovis) infection is regarded as harmful to the host because it promotes the spread of M. bovis. Ferroptosis is a controlled type of cell death that occurs when there is an excessive buildup of both free iron and harmful lipid peroxides. Here, we demonstrate that the mammalian cell entry (Mce) 4 family protein Mb3523c triggers ferroptosis to promote M. bovis pathogenicity and dissemination. Mechanistically, Mb3523c, through its Y237 and G241 site, interacts with host HSP90 protein to stabilize the LAMP2A on the lysosome to promote the chaperone-mediated autophagy (CMA) pathway. Then, GPX4 is delivered to lysosomes for destruction via the CMA pathway, eventually inducing ferroptosis to promote M. bovis transmission. In summary, our findings offer novel insights into the molecular mechanisms of pathogen-induced ferroptosis, demonstrating that targeting the GPX4-dependent ferroptosis through blocking the M. bovis Mb3523c-host HSP90 interface represents a potential therapeutic strategy for tuberculosis (TB).Abbreviations: CFU: colony-forming units; CMA: chaperone-mediated autophagy; Co-IP: co-immunoprecipitation; Fer-1: ferrostatin-1; GPX4: glutathione peroxidase 4; HSP90: heat shock protein 90; LDH: lactate dehydrogenase; Mce: mammalian cell entry; MOI: multiplicity of infection; Nec-1: necrostatin-1; PI: propidium iodide; RCD: regulated cell death.

Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer's disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer's disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer's disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer's disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer's disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer's disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer's disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer's disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer's disease.

Lung cancer remains a major global health challenge and one of the leading causes of cancer-related deaths worldwide. Despite significant advancements in treatment, challenges such as drug resistance, side effects, metastasis and recurrence continue to impact patient outcomes and quality of life. In response, there is growing interest in complementary and integrative approaches to cancer care. Traditional Chinese medicine (TCM), with its long history, abundant clinical experience, holistic perspective and individualized approach, has garnered increasing attention for its role in lung cancer prevention and management. This review provides a comprehensive overview of the advances in TCM for lung cancer treatment, covering its theoretical foundation, treatment principles, clinical experiences and evidence supporting its efficacy. We also provide a systematic summary of the preclinical mechanisms, through which TCM impacts lung cancer, including the induction of cell death, reversal of drug resistance, inhibition of metastasis and modulation of immune responses. Additionally, future prospects for TCM in lung cancer treatment are discussed, offering insights into its expanded application and integration with modern medicine to address this challenging disease.

Chinese herbal medicine constitutes a substantial cultural and scientific resource for the Chinese nation, attracting considerable scholarly interest due to its intrinsic characteristics of "multi-component, multi-target, and multi-pathway" interactions. Simultaneously, it aligns accurately with the intricate and continuously evolving progression of non-small cell lung cancer (NSCLC). Furthermore, contemporary pharmacological studies indicate that natural herbaceous plants and their bioactive compounds exhibit a diverse array of biological activities, including antioxidant, anti-inflammatory, and anti-tumor effects, among others. Additionally, these substances have been demonstrated to possess a degree of safety, particularly in terms of exhibiting comparatively lower levels of toxicity to the liver and kidneys when contrasted with conventional Western medicine. Thus, the development of herbal plants, which includes both single herbs and composite formulations, as well as their bioactive constituents, through the targeted regulation of ferroptosis and mitophagy, presents substantial potential and instills considerable hope for individuals diagnosed with NSCLC.

This review aims to conduct a critical analysis of the ethnopharmacological applications of natural herbaceous plants in relation to ferroptosis and mitophagy in NSCLC. The objective is to evaluate the potential advantages of prioritizing specific phytochemical constituents found in these plants, which may serve as novel therapeutic candidates informed by ethnobotanical knowledge. Additionally, this study seeks to enhance the current pharmacological applications of natural herbaceous plants.

An investigation into natural herbal remedies for NSCLC was conducted, with a particular emphasis on the ferroptosis and mitophagy pathways. This study utilized traditional medical texts and ethnomedicinal literature as primary sources. Furthermore, relevant information related to ethnobotany, phytochemistry, and pharmacology is obtained from online databases, including PubMed and the China National Knowledge Infrastructure (CNKI), among others. "Traditional Chinese medicine compound preparations", "single herb extracts", "active compounds", "NSCLC", "ferroptosis", and "mitophagy" were used as keywords when searching the databases. Consequently, pertinent articles published in recent years were collected and analyzed.

Given the complex etiology of NSCLC, treatment strategies that concentrate exclusively on ferroptosis or mitophagy often demonstrate limitations. In this regard, the utilization of herbal plants offers unique benefits in the management of NSCLC. The rationale can be summarized within the following two dimensions: Firstly, due to the molecular mechanisms of ferroptosis and mitophagy involving multiple signaling pathways (including PINK1/Parkin, HMGB1, system Xc-/GPX4/GSH, FSP1/CoQ10/NAD (P) H, and so on), sometimes drugs with a single target are difficult to involve multiple pathways. Fortunately, there is an expanding body of evidence suggesting that various herbaceous plants and their bioactive compounds can affect multiple biological targets. Moreover, these compounds seem to interact with several targets associated with ferroptosis and mitophagy in NSCLC (such as NIX, BNIP3, FUNDC1, GPX4, FSP1, P53, Nrf2, LncRNA, and so on). Secondly, Herbaceous plants and their bioactive compounds have been shown to possess a favorable safety profile, particularly with respect to reduced hepatotoxicity and nephrotoxicity in comparison to conventional Western medicine. For example, Numerous compound formulations, such as Fangji Huangqi decoction, Mufangji decoction, Qiyu Sanlong decoction, and Fuzheng Kangai decoction, have been employed in China for millennia, and their clinical efficacy appears to be quite promising. Notably, In recent years, numerous researchers have sought to isolate active constituents from clinically effective compound formulations through the application of chemical methodologies. This endeavor has been driven by the necessity to tackle challenges related to complex ingredient compositions and sophisticated processing. These active compounds have been employed in cellular and animal studies to elucidate the molecular mechanisms underlying these formulations.

The Asian region has a long-standing historical tradition of employing natural herbaceous plants for traditional medicinal purposes. Phytochemical and pharmacological studies have shown that various compound preparations derived from traditional Chinese medicine, along with individual herb extracts and their active constituents, display a range of bioactive effects. These effects encompass anti-tumor, anti-inflammatory, antibacterial, and antioxidant properties, among others. Numerous traditional compound formulations originating from China have emerged as promising candidates for the development of pharmacological agents targeting NSCLC. It is noteworthy that a variety of compound formulations aimed at the ferroptosis and mitophagy pathways, which demonstrate unique therapeutic effects on NSCLC, are presently under extensive investigation by an increasing number of researchers. Therefore, it is imperative to consider in vitro mechanistic studies, in vivo pharmacological evaluations, and assessments of clinical efficacy. Furthermore, it is essential to conduct a comprehensive assessment of plant resources, implement quality control measures, and engage in toxicological research to ensure that the data is appropriate for further examination.

Manzamine A (MA), a bioactive compound derived from the marine sponge Haliclona sp., shows considerable therapeutic potential, particularly in the treatment of various cancer types. Extracted with acetone and purified through chromatography, MA exhibits a bioavailability of 20.6% when administered orally in rats, underscoring its feasibility for therapeutic use. This compound disrupts key cellular mechanisms essential for cancer progression, including microtubule dynamics and DNA replication enzymes, demonstrating strong anti-proliferative effects against multiple cancer cell lines while sparing normal cells. Additionally, network pharmacology and molecular docking studies reveal MA's interactions with important targets related to lung cancer progression, such as EGFR and SRC, bolstering its potential as a novel anti-lung cancer agent. Pathway analyses further indicate that MA influences critical signaling pathways involved in tumor growth and metastasis. Given the urgent need for effective treatments against drug-resistant cancers and the limited toxicity profile of MA, further exploration of its pharmacological benefits and mechanism could pave the way for new therapeutic strategies in lung cancer.

Ferroptosis, a form of regulated cell death, is characterized by iron-dependent lipid peroxidation. It is recognized increasingly for its pivotal role in both cancer development and the response to cancer treatments. We assessed associations between 370,027 single-nucleotide polymorphisms (SNPs) within 467 ferroptosis-related genes and survival of non-small cell lung cancer (NSCLC) patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial served as our discovery dataset, while the Harvard Lung Cancer Susceptibility Study used as our validation dataset. For SNPs that remained statistically significantly associated with overall survival (OS) in both datasets, we employed a multivariable stepwise Cox proportional hazards regression model with the PLCO dataset. Ultimately, two independent SNPs, PARK7 rs225120 C>T and DDR2 rs881127 T>C, were identified with adjusted hazard ratios of 1.32 (95% confidence interval = 1.15-1.52, p = .0001) and 1.34 (95% confidence interval = 1.09-1.64, p = .006) for OS, respectively. We aggregated these two SNPs into a genetic score reflecting the number of unfavorable genotypes (NUG) in further multivariable analysis, revealing a noteworthy association between increased NUG and diminished OS (ptrend = .001). Additionally, an expression quantitative trait loci analysis indicated that PARK7 rs225120T genotypes were significantly associated with higher PARK7 mRNA expression levels in both whole blood and normal lung tissue. Conversely, DDR2 rs881127C genotypes were significantly associated with lower DDR2 mRNA expression levels in normal lung tissue. Our findings suggest that genetic variants in the ferroptosis-related genes PARK7 and DDR2 are associated with NSCLC survival, potentially through their influence on gene expression levels.

Streptococcus suis (S. suis) is a major swine pathogen throughout the world as well as an emerging zoonotic agent. Among the symptoms caused by S. suis, including septicemia, pneumonia, endo-carditis, arthritis, and meningitis, the latter is the most overlooked. In the present study, we explored the mechanism of action of berberine against S. suis meningitis by obtaining berberine-related action targets, porcine S. suis meningitis targets, and human S. suis meningitis targets from open databases. We constructed a protein-protein interaction (PPI) network by using the STRING database and employed Cytoscape 3.8.0 to screen for core targets. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses through DAVID. We identified 31 potential targets of berberine, of which Toll-like receptor 4 (TLR4), fibronectin 1 (FN1), superoxide dismutase (SOD1), and catalase (CAT) were the four most critical targets. GO analysis revealed the enrichment of terms related to the response to oxidative stress and the inflammatory response. KEGG analysis revealed the enrichment of the interleukin 17 (IL-17), phosphoinositide 3-kinase (PI3K)-Akt, TLR, tumor necrosis factor (TNF), and mitogen-activated protein kinase (MAPK) signaling pathways. In addition, the admetSAR results showed that berberine can cross the blood-brain barrier. The molecular docking results indicated key binding activity between TLR4-berberine and FN1-berberine. In summary, berberine protects against Streptococcus suis meningitis by regulating inflammatory response and oxidative stress in humans and pigs. Our study updates the current knowledge of the targets of S. suis meningitis to exploit new drugs in humans and pigs, to develop environmentally friendly and antibiotic-free animal-derived food products, and to improve the farming industry and economic development.

The rhizome of Curcuma phaeocaulis Valeton, Curcuma wenyujin Y.H. Chen & C. Ling, or Curcuma kwangsiensis S. G. Lee et C. F. Liang, commonly known as Wen-E-Zhu and E'zhu, has been utilized in traditional Chinese medicine for the treatment of cancer and gynecological diseases since antiquity. This traditional medicinal herb is highly esteemed for its efficacy in promoting blood circulation, dissolving blood stasis, reducing swelling, and alleviating pain. β-Elemene (β-ELE), a sesquiterpene compound derived from Curcuma phaeocaulis, has demonstrated potential in inhibiting tumor cell proliferation and inducing ferroptosis, which have been extensively studied in various malignant neoplasms. Previous studies have confirmed that Sparganium stoloniferum-Curcuma phaeocaulis containing β-ELE may possess anti-endometriotic properties. However, the exact mechanism underlying β-ELE's anti-endometriosis activity remains largely unknown and requires further research and investigation.

To identify the anti-endometriosis target of β-ELE and elucidate the underlying molecular mechanism of β-ELE in endometriosis, focusing on inducing ferroptosis.

The target pathway of β-ELE in endometriosis treatment was predicted through network pharmacology and bioinformatics analysis. Surface plasmon resonance-high performance liquid chromatography-protein mass spectrometry (SPR-HPLC-MS) and molecular docking were used to further identify the potential targets of β-ELE in endometriosis. The immortalized endometriosis epithelial cell line 12Z was used for in vitro study. The effect of β-ELE on cell proliferation and migration was detected by CCK-8, EdU and wound healing assay, and ultrastructural changes were examined via transmission electron microscopy. The effect of β-ELE-induced ferroptosis was determined by western blot, immunohistochemistry staining and flow cytometry. SPR affinity analysis was performed to specific the direct interaction between β-ELE and FTH1, FTL, GPX4, STAT3 and MAPK14. To establish a mouse model of endometriosis and to assess the inhibitory effects of β-ELE and ELE injection on endometriosis in vivo as well as safety profile of administration, and investigate the effects and underlying mechanisms of β-ELE and ELE injection on ferroptosis in ectopic lesions.

SPR-HPLC-MS was employed to identify 76 potential targets of β-ELE for endometriosis treatment, closely linked to ferroptosis. Molecular docking revealed that glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinase 14 (MAPK14) are key action targets of β-ELE in endometriosis. Further investigations revealed that β-ELE inhibited the proliferation and migration of endometriotic cells in vitro while inducing ferroptosis, as evidenced by increased levels of iron, reactive oxygen species (ROS), and lipid peroxidation. In a mouse model, β-ELE inhibited the growth of endometriotic lesions, induced ferroptosis, suppressed fibrosis, and exhibited anti-endometriotic effects. Mechanistically, β-ELE downregulates the expression levels of GPX4, FTH1, and FTL and inhibited the phosphorylation of STAT3 and MAPK14, which may elucidate its underlying molecular mechanisms.

This study demonstrates that the inhibitory effect of β-ELE on endometriosis by inducing ferroptosis in vitro and in vivo. Our results revealed that β-ELE exerts anti-endometriosis effects by inducing ferroptosis via the MAPK and STAT3 signaling pathways.

Airway remodeling in chronic obstructive pulmonary disease (COPD) is a contributor to airflow limitation, promotes disease progression, and affects disease outcome and prognosis. Quercetin has been identified as a potential therapeutic agent for COPD. Currently, there is insufficient research providing direct evidence to support this hypothesis. The present study investigates the therapeutic effects and the underlying mechanisms of quercetin in the alleviation of airway remodeling in rat models of COPD.

This study used a network pharmacology approach to predict, for the first time, the potential molecular targets of quercetin in COPD. The effects of quercetin on phenotypic switching and mitochondrial function of ASMCs were assessed in vitro using CCK-8, EdU staining, migration assays, western blotting, and JC-1 staining. Additionally, the interaction between Wnt5a and quercetin was analyzed via molecular docking, and findings were experimentally confirmed using the cellular thermal shift assay (CETSA). Quercetin's influence on airway remodeling in COPD was examined in vivo through pulmonary function evaluation, H&E staining, and Modified Sirius Red staining. Molecular alterations associated with phenotypic switching, oxidative stress, autophagy and Wnt5a/β-Catenin pathway were examined by Western blotting, immunofluorescence, immunohistochemistry, DHE staining and ELISA.

The results showed that quercetin has a beneficial therapeutic effect on COPD. Its ability to mitigate airway remodeling is linked to modulating autophagy levels, reducing oxidative stress, alleviating mitochondrial damage, and influencing the phenotypic switch in ASMCs. By increasing oxidative stress tolerance, quercetin reduces mitochondrial damage and regulates the phenotypic switch in ASMCs. Furthermore, quercetin suppresses autophagy hyperactivation, which subsequently lowers oxidative stress levels in ASMCs. Notably, quercetin modulates autophagy through the regulation of the Wnt5a/β-catenin signaling pathway.

In conclusion, quercetin demonstrates potential therapeutic effects in COPD by suppressing the Wnt5a/β-cateninsignaling pathway, autophagy as well as oxidative stress, and thereby alleviating mitochondrial damage and the phenotypic switch in ASMCs. These findings may have clinical applications and offer new insights for the development of COPD treatments.

Colorectal cancer (CRC) continues to represent a significant global public health challenge. Ferroptosis, a novel form of cell death dependent on iron and involving lipid peroxidation, has emerged as an effective strategy for treating various cancers with great potential for application.

This study aimed to investigate the therapeutic potential of erianin, a novel dibenzyl compound isolated from the well-known herbal medicine Dendrobium chrysotoxum Lindl, in the treatment of CRC through induction of ferroptosis.

Human CRC HCT116 and SW480 cells were employed for in vitro investigations, while an AOM/DSS CRC animal model was established for in vivo experiments.

The results demonstrated that erianin effectively inhibited the growth of CRC cells and suppressed tumorigenesis in the AOM/DSS CRC animal model. Erianin induced ferroptosis in CRC cells as evidenced by a significant increase in intracellular Fe2+ levels and lipid peroxides, along with a decrease in glutathione. Additionally, ferroptosis inhibitors reversed the cytotoxicity of erianin against CRC cells as well as its induction of ferroptosis. Notably, novel glutathione peroxidase 4 (GPX4), a core regulatory factor of ferroptosis, was found to be overexpressed in human primary colon adenocarcinoma tissues compared with normal tissues. However, erianin significantly reduced GPX4 expression by facilitating its ubiquitination and degradation. Furthermore, the overexpression of GPX4 mitigated erianin-induced ferroptotic cell death; conversely, the silencing of GPX4 amplified these effects.

Erianin demonstrates the potential to inhibit CRC by inducing ferroptosis through accelerating the ubiquitination and degradation of GPX4, indicating its promise as a therapeutic candidate against CRC.

To construct a prediction model consisting of metabolites and proteins in peripheral blood plasma to predict whether patients with unresectable stage III and IV non-small cell lung cancer can benefit from immunotherapy before it is administered.

Peripheral blood plasma was collected from unresectable stage III and IV non-small cell lung cancer patients who were negative for driver mutations before receiving immunotherapy. Then we classified samples according to the follow-up results after two courses of immunotherapy and non-targeted metabolomics and proteomics analyses were performed to select different metabolites and proteins. Finally, potential biomarkers were picked out by applying machine learning methods including random forest and stepwise regression and prediction models were constructed by logistic regression.

The presence of metabolites and proteins in peripheral blood plasma was causally associated with both non-small cell lung cancer and PD-L1/PD-1 expression levels. A total of 2 differential metabolites including 5-sulfooxymethylfurfural and Anthranilic acid and 2 differential proteins including Immunoglobulin heavy variable 1-45 and Microfibril-associated glycoprotein 4 were selected as reliable biomarkers. The area under the curve (AUC) of the prediction model built on clinical risks was merely 0.659. The AUC of metabolomics prediction model was 0.977 and the AUC of proteomics was 0.875 while the AUC of the integrative-omics prediction model was 0.955.

Metabolic and protein biomarkers in peripheral blood both have high efficacy and reliability in the prediction of immunotherapy sensitivity in unresectable stage III and IV non-small cell lung cancer, but validation in larger population-based cohorts is still needed.

Pain, a complex symptom encompassing both sensory and emotional dimensions, constitutes a significant global public health issue. Oxidative stress is a pivotal factor in the complex pathophysiology of pain, with glutathione peroxidase 4 (GPX4) recognized as a crucial antioxidant enzyme involved in both antioxidant defense mechanisms and ferroptosis pathways. This review systematically explores GPX4's functions across various pain models, including neuropathic, inflammatory, low back, and cancer-related pain. Specifically, the focus includes GPX4's physiological roles, antioxidant defense mechanisms, regulation of ferroptosis, involvement in signal transduction pathways, and metabolic regulation. By summarizing current research, we highlight the potential of GPX4-targeted therapies in pain management.

Sustained myocardial hypertrophy or left ventricular hypertrophy (LVH) triggered by pressure overload is strongly linked to adverse cardiovascular outcomes. Here, we investigated the clinical relationship between serum HSP90α (an isoform of HSP90) levels and LVH in patients with hypertension or aortic stenosis (AS) and explored underlying mechanisms in pressure overload mouse model. We built a pressure overload mouse model via transverse aortic constriction (TAC). Compared to controls, elevated serum HSP90α levels were observed in patients with hypertension or AS, and the levels positively correlated with LVH. Similarly, HSP90α levels increased in heart tissues from patients with obstructive hypertrophic cardiomyopathy (HCM), and in mice post-TAC. TAC induced the enhanced cardiac expression and secretion of HSP90α from cardiomyocytes and cardiac fibroblasts. Knockdown of HSP90α or blockade of extracellular HSP90α (eHSP90α) attenuated cardiac hypertrophy and dysfunction by inhibition of β-catenin/TCF7 signaling under pressure overload. Further analysis revealed that eHSP90α interacted with EC1-EC2 region of N-cadherin to activate β-catenin, enhancing the transcription of hypertrophic genes by TCF7, resulting in cardiac hypertrophy and dysfunction under pressure overload. These insights suggest the therapeutic potential of targeting HSP90α-initiated signaling pathway against cardiac hypertrophy and heart failure under pressure overload.

Timosaponins, as steroidal saponins, are the primary active constituents and quality biomarkers in Anemarrhena asphodeloides Bunge. Despite their significance, the biosynthetic pathways of timosaponins have not been thoroughly investigated.

This study aims to delineate the biosynthetic pathway of timosaponins in A. asphodeloides, elucidate the catalytic mechanisms of the key cycloartenol synthase (CAS), and investigate the antifungal properties of timosaponins.

Genes were cloned from A. asphodeloides and heterologous expressed in yeast, tobacco or bacillus coli. Site-directed mutagenesis and molecular docking were used to elucidate the catalytic mechanism of CAS. Antifungal assays were conducted to evaluate the antifungal activities of timosaponins.

In this study, we elucidated the biochemical functions of seven genes involved in timosaponins biosynthesis in A. asphodeloides. Among three candidate OSC genes, AaOSCR12 was identified as the gene encoding cycloartenol synthase, which is responsible for the skeleton cyclization in timosaponin biosynthesis. Six residues (257H, 369N, 448T, 507V, 558P, 616Y) were identified as the critical catalytic active sites of CAS (AaOSCR12). Sterol methyltransferase (AaSMT1) and sterol side-chain reductase (AaSSR2) were found to be the subsequent enzymes and the branching points leading to phytosterol and cholesterol biosynthesis, respectively. Two oxide reductase genes, AaCYP90B27 and AaCYP90B2, were responsible for post-modification of cholesterol, serving as a precursor of timosaponins. A key 26-O-β-glucosidase (AaF26G1) was identified as facilitating the conversion of furostanol-type timosaponins into spirostanol-type timosaponins. Antifungal assays revealed that spirostanol-type timosaponin III exhibits superior antifungal activity compared to furostanol-type timosaponin II, potentially linked to plant defense mechanisms involving AaF26G1.

This study utilized a multi-chassis cross-identification strategy, revealing key enzymes in the timosaponin biosynthetic pathway and offering novel insights into plant defense mechanisms against microbial pathogens.

Lung carcinoma incidence and fatality rates remain among the highest on a global scale. The efficacy of targeted therapies and immunotherapies is commonly compromised by the emergence of drug resistance and other factors, resulting in a lack of durable therapeutic benefits. Ferroptosis, a distinct pattern of cell death marked by the buildup of iron-dependent lipid peroxides, has been shown to be a novel and potentially more effective treatment for lung carcinoma. However, the mechanism and regulatory network of ferroptosis are exceptionally complex, and many unanswered questions remain. In addition, research on ferroptosis in the diagnosis and treatment of lung cancer has been growing exponentially. Therefore, it is necessary to provide a thorough summary of the latest advancements in the field of ferroptosis. Here, we comprehensively analyze the mechanisms underlying the preconditions of ferroptosis, the defense system, and the associated molecular networks. The potential strategies of ferroptosis in the treatment of lung carcinoma are also highlighted. Targeting ferroptosis improves tumor cell drug resistance and enhances the effectiveness of targeted drugs and immunotherapies. These findings may shed fresh light on the diagnosis and management of lung carcinoma, as well as the development of drugs related to ferroptosis.

Macrophages play an important role in the pathogenesis of ulcerative colitis (UC). We will explore the effects of sodium butyrate (SB) on macrophage function.

The targets of butyric acid were identified using SwissTargetPrediction database and surface plasmon resonance (SPR). Limited proteolysis mass spectrometry (Lip-MS) was used to further investigate the binding sites of butyric acid with its targets and molecular docking was employed to simulate their binding modes. Macrophage polarization model was established with lipopolysaccharide (LPS) in vitro. Takeda G protein-coupled receptor 5 (TGR5) and β-arrestin2 expression and macrophage polarization markers were detected with or without SB.

TGR5 was identified as the target of butyric acid. Moreover, the amino acid regions 275-286 and 321-330 of TGR5 (GPBAR1 [275-286] and GPBAR1 [321-330]) were the potential binding regions for butyric acid. Based on molecular docking analysis, butyric acid formed effective hydrogen-bonding interactions with ASP-284 and TYR-287 of TGR5. In cell experiments, LPS inhibited the expression of TGR5, β-arrestin2, IL-10, ARG1, and CD206 and increased the expression of IL-1β, iNOS, and CD86, while SB reversed the effect of LPS. SBI-115, a TGR5 antagonist, and knockdown of β-arrestin2 inhibited the effect of sodium butyrate. INT-777, a TGR5 agonist, reversed the inhibitory effect of knockdown of β-arrestin2.

SB inhibited M1-like polarization and promoted M2-like polarization induced by LPS via TGR5/β-arrestin2 in RAW264.7 cells and TGR5 was the target of SB.

Endometrial cancer (EC) is a common malignant tumor that is closely associated with metabolic disorders such as diabetes and obesity. Advanced glycation end products (AGEs) are complex polymers formed by the reaction of reducing sugars with the amino groups of biomacromolecules, mediating the occurrence and development of many chronic metabolic diseases. Recent research has demonstrated that the accumulation of AGEs can affect the tumor microenvironment, metabolism, and signaling pathways, thereby affecting the malignant progression of tumors. However, the mechanism by which AGEs affect EC is unclear. Our research aimed to investigate how AGEs promote the development of EC through metabolic pathways and to explore their potential underlying mechanisms. Our experimental results demonstrated that AGEs upregulated the choline metabolism mediated by choline kinase alpha (CHKA) through the receptor for advanced glycation end products, activating the PI3K/AKT pathway and enhancing the malignant biological behavior of EC cells. Virtual screening and molecular dynamics simulation revealed that timosaponin A3 could target CHKA to inhibit AGE-induced progression of EC and that a newly discovered CHKA inhibitor could be a novel targeted inhibitor for the treatment of EC. This study provides new therapeutic strategies and contributes to the treatment of EC.

Abnormal cholesterol metabolism has become a popular therapeutic target in cancer therapy. In recent years there has been a surge in interest in the anti-tumor activities of saponins, particularly their ability to disrupt cholesterol homeostasis in tumor cells. Cholesterol regulation by saponins is a complex process that involves multiple mechanisms. However, there are now a notable dearth of comprehensive reviews addressing their anti-tumor effects through cholesterol modulation. This review will explore the intricate mechanisms by which saponins regulate cholesterol, including modulation of synthesis, metabolism, and uptake, as well as complex formation with cholesterol. It will also outline how saponins exert their anti-cancer activities through cholesterol regulation, enhancing cytotoxicity, inhibiting tumor cell metastasis, reversing drug resistance, inducing immunotoxin macromolecule escape, and ferroptosis. This comprehensive analysis offers insights into the potential for the use of saponins anti-tumor therapies and their combinations with other drugs, advancing the understanding of their effects on cancer cells.

Ferroptosis is a form of cell death elicited by an imbalance in intracellular iron concentrations, leading to enhanced lipid peroxidation. In neurological disorders, both oxidative stress and mitochondrial damage can contribute to ferroptosis, resulting in nerve cell dysfunction and death. The ubiquitin-proteasome system (UPS) refers to a cellular pathway in which specific proteins are tagged with ubiquitin for recognition and degradation by the proteasome. In neurological conditions, the UPS plays a significant role in regulating ferroptosis. In this review, we outline how the UPS regulates iron metabolism, ferroptosis, and their interplay in neurological diseases. In addition, we discuss the future application of small-molecule inhibitors and identify potential drug targets. Further investigation into the mechanisms of UPS-mediated ferroptosis will provide novel insights and strategies for therapeutic interventions and clinical applications in neurological diseases.

As a crucial regulator of oxidative homeostasis, seleno-protein glutathione peroxidase 4 (GPX4) represents the primary defense system against ferroptosis, making it a promising target with important clinical application prospects. From the discovery of covalent and allosteric sites in GPX4, substantial advancements in GPX4-targeted small molecules have been made through diverse discovery and design strategies in recent years. Moreover, as an emerging hotspot in drug development, seleno-organic compounds can functionally mimic GPX4 to reduce hydroperoxides. To facilitate the further development of selective ferroptosis mediators as potential pharmaceutical agents, this review comprehensively covers all GPX4-targeted small molecules, including inhibitors, degraders, and activators. In addition, seleno-organic compounds as GPX mimics are also included. We also provide perspectives regarding challenges and future research directions in this field.

While higher therapeutic doses of toxic cardiac glycosides derived from Cerbera odollam are frequently employed in cases of suicide or homicide, ongoing research is investigating the potential anticancer properties of low-concentration extracts obtained from the fruits of C. odollam. The present study aimed to determine the enhanced anticancer effects and minimize potential side effects of combining extracts from C. odollam fruits from Thailand with sorafenib against HCT116 and HepG2 cells.

The dried powder of fresh green fruits of C. odollam was fractionated, and its phytochemical contents, including total cardiac glycosides, phenolics, flavonoids, and triterpenoids, were quantified. The cytotoxic effects of these fractions were evaluated against HCT116 and HepG2 cells using the MTT assay. The fractions showing the most significant response in HCT116 and HepG2 cells were subsequently combined with sorafenib to examine their synergistic effects. Apoptosis induction, cell cycle progression, and mitochondrial membrane potential (MMP) were then assessed. The underlying mechanism of the apoptotic effect was further investigated by analyzing reactive oxygen species (ROS) generation and the expression levels of antioxidant proteins.

Phytochemical analysis showed that C. odollam-ethyl acetate fraction (COEtOAc) was rich in cardiac glycosides, phenolics, and flavonoids, while the dichloromethane fraction (CODCM) contained high levels of triterpenoids and saponins. Following 24 h treatment, HCT116 showed the most significant response to COEtOAc, while HepG2 responded well to CODCM with IC50 values of (42.04 ± 16.94) μg/mL and (123.75 ± 14.21) μg/mL, respectively. Consequently, COEtOAc (20 μg/mL) or CODCM (30 μg/mL), both administered at sub-IC50 concentrations, were combined with sorafenib at 6 μmol/L for HCT116 cells and 2 μmol/L for HepG2 cells, incubated for 24 h. This combination resulted in a significant suppression in cell viability by approximately 50%. The combination of treatments markedly enhanced apoptosis, diminished MMP, and triggered G0/G1 phase cell cycle arrest compared to the effects of each treatment administered individually. Concurrently, increased formation of ROS and decreased expression of the antioxidant enzymes superoxide dismutase 2 and catalase supported the proposed mechanism of apoptosis induction by the combination treatment. Importantly, the anticancer effect demonstrated a specific targeted action with a favorable safety profile, as evidenced by HFF-1 cells displaying IC50 values 2-3 times higher than those of the cancer cells.

Utilizing sub-IC50 concentrations of COEtOAc or CODCM in combination with sorafenib can enhance targeted anticancer effects beyond those achieved with single-agent treatments, while mitigating opposing side effects. Future research will focus on extracting and characterizing active constituents, especially cardiac glycosides, to enhance the therapeutic potential of anticancer compounds derived from toxic plants.

Ferroptosis is a novel type of programmed cell death that relies on the build-up of intracellular iron and leads to an increase in toxic lipid peroxides. Glutathione Peroxidase 4 (GPX4) is a crucial regulator of ferroptosis that uses glutathione as a cofactor to detoxify cellular lipid peroxidation. Targeting GPX4 in cancer could be a promising strategy to induce ferroptosis and kill drugresistant cancers effectively. Currently, research on GPX4 inhibitors is of increasing interest in the field of anti-tumor agents. Many reviews have summarized the regulation and ferroptosis induction of GPX4 in human cancer and disease. However, insufficient attention has been paid to GPX4 inhibitors. This article outlines the molecular structures and development prospects of GPX4 inhibitors as novel anticancer agents.

Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and their polarization state significantly influences patient outcomes. This study investigates the inhibitory effects of β-glucan extracted from Candida albicans on lung cancer progression, focusing on its impact on TAM polarization and the induction of ferroptosis, a form of regulated cell death.

Utilizing both in vivo animal models and in vitro cellular assays, we assessed the impact of β-glucan on tumor growth, cellular proliferation, and migration. We evaluated TAM polarization by analyzing the expression of M1 and M2 markers and identified differentially expressed genes (DEGs) related to ferroptosis. The role of ferroptosis in TAM polarization was further confirmed by assessing the protein levels of ACSL4 and GPX4, intracellular ferrous ion levels, and lipid peroxides.

β-glucan treatment significantly reduced tumor size and weight, along with cellular proliferation and migration, suggesting a potent suppressive effect on lung cancer cell growth. β-glucan promoted an M1-like phenotype in TAMs, as evidenced by increased CD86 expression and decreased CD206 expression, and modulated cytokine mRNA levels. RNA sequencing analysis post β-glucan treatment identified a substantial number of DEGs enriched in the ferroptosis pathway. The induction of ferroptosis by β-glucan was further confirmed through the significant upregulation of ACSL4 and downregulation of GPX4, alongside increased intracellular ferrous ion levels and lipid peroxides. The ferroptosis inhibitor Fer-1 abrogated these effects, highlighting the specificity of β-glucan-mediated polarization.

These results collectively provide novel insights into the immunotherapeutic potential of β-glucan from Candida albicans and its role in modulating TAM polarization and lung cancer growth, offering a promising avenue for cancer treatment strategies.

This review endeavors to elucidate the complex interplay underlying diseases associated with ferroptosis and to delineate the multifaceted mechanisms by which triterpenoid and steroidal saponins modulate this form of cell death.

A meticulous examination of the literature was undertaken, drawing from an array of databases including Web of Science, PubMed, and Wiley Library, with a focus on the keywords "ferroptosis," "saponin," "cancer," "inflammation," "natural products," and "signaling pathways."

Ferroptosis represents a distinctive mode of cell death that holds considerable promise for the development of innovative therapeutic strategies targeting a wide range of diseases, especially cancer and inflammatory disorders. This review reveals the nuanced interactions between saponins and critical signaling pathways, including system Xc--GSH-GPX4, Nrf2, p53, and mTOR. These interactions highlight the dual capacity of saponins to modulate ferroptosis, thereby offering fresh perspectives for therapeutic intervention.

The insights garnered from this review significantly advance our comprehension of the dynamic relationship between saponins and ferroptosis. By shedding light on these mechanisms, this work sets the stage for leveraging these insights in the creation of pioneering approaches to disease treatment, marking a significant stride in the evolution of therapeutic modalities.

Cancer is a multifaceted disease influenced by various mechanisms, including the generation of reactive oxygen species (ROS), which have a paradoxical role in both promoting cancer progression and serving as targets for therapeutic interventions. At low concentrations, ROS serve as signaling agents that enhance cancer cell proliferation, migration, and resistance to drugs. However, at elevated levels, ROS induce oxidative stress, causing damage to biomolecules and leading to cell death. Cancer cells have developed mechanisms to manage ROS levels, including activating pathways such as NRF2, NF-κB, and PI3K/Akt. This review explores the relationship between ROS and cancer, focusing on cell death mechanisms like apoptosis, ferroptosis, and autophagy, highlighting the potential therapeutic strategies that exploit ROS to target cancer cells.

Calotropis gigantea (L.) Dryand. (C. gigantea) is a traditional medicinal plant, recognized for its effectiveness in managing diabetes, along with its notable antioxidant, anti-inflammatory, and anticancer properties. Type II diabetes mellitus (T2DM) is characterized by chronic metabolic disorders associated with an elevated risk of hepatocellular carcinoma (HCC) due to hyperglycemia and impaired insulin response. The scientific validation of C. gigantea's ethnopharmacological efficacy offers advantages in alleviating cancer progression in T2DM complications, enriching existing knowledge and potentially aiding future clinical cancer treatments.

This study aimed to investigate the preventive potential of the dichloromethane fraction of C. gigantea stem bark extract (CGDCM) against diethylnitrosamine (DEN)-induced HCC in T2DM rats, aiming to reduce cancer incidence associated with diabetes while validating C. gigantea's ethnopharmacological efficacy.

Spontaneously Diabetic Torii (SDT) rats were administered DEN to induce HCC (SDT-DEN-VEH), followed by treatment with CGDCM. Metformin was used as a positive control (SDT-DEN-MET). All the treatments were administered for 10 weeks after the initial DEN injection. Diabetes-related parameters, including serum levels of glucose, insulin, and glycosylated hemoglobin (HbA1c), as well as liver function enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase), were quantified. Serum inflammation biomarkers interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were evaluated. Liver tissue samples were analyzed for inflammation protein expression (IL-6, TNF-α, transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin (α-SMA)). Histopathological evaluation was performed to assess hepatic necrosis, inflammation, and fibrosis. Liver cell proliferation was determined using immunohistochemistry for Ki-67 expression.

Rats with SDT-DEN-induced HCC treated with CGDCM exhibited reduced serum glucose levels, elevated insulin levels, and decreased HbA1c levels. CGDCM treatment also reduced elevated hepatic IL-6, TNF-α, TGF-β1, and α-SMA levels in SDT-DEN-VEH rats. Additionally, CGDCM treatment prevented hepatocyte damage, fibrosis, and cell proliferation. No adverse effects on normal organs were observed with CGDCM treatment, suggesting its safety for the treatment of HCC complications associated with diabetes. Additionally, the absence of adverse effects in SD rats treated with CGDCM at 2.5 mg/kg further supports the notion of its safe usage.

These findings suggest that C. gigantea stem bark extract exerts preventive effects against the development of HCC complications in patients with T2DM, expanding the potential benefits of its ethnopharmacological advantages.

Bladder cancer (BLCA) remains a significant health risk despite advancements in medical science that have led to reduced incidence and death rates. While the molecular regulatory mechanisms of BLCA are not yet fully understood, HSPE1, a member of the heat shock protein family, is regarded as a reliable prognostic target for BLCA. Using data from The Cancer Genome Atlas (TCGA) database, the differential expression levels of HSPE1 and its relationship to GPX4 were examined. Gene Set Enrichment Analysis was used to carry out HSPE1 pathway enrichment analysis. HSPE1 and GPX4 expressions in cells were assessed using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting. Cell cycle alternations and apoptosis were evaluated using flow cytometry. Cell proliferation was assessed using EdU and colony formation assays. The lactate dehydrogenase (LDH) test, glutathione (GSH) measurement, and Liperfluo assay were utilized to evaluate the presence of ferroptosis in cells. BLCA tissues and cells had significantly elevated levels of HSPE1. In BLCA, high expression of HSPE1 inhibited apoptosis while promoting cell proliferation and cell cycle progression. Significant enrichment of HSPE1 was found in the GSH metabolism and ferroptosis pathways, according to pathway enrichment analysis. In cancer cells, HSPE1 promoted GSH accumulation, decreased lipid peroxidation, and inhibited cell ferroptosis, as demonstrated in a rescue experiment with the ferroptosis inhibitor Fer-1. Pearson correlation analysis unveiled a substantial positive correlation between HSPE1 and the ferroptosis regulator GPX4. According to the results of rescue experiments, HSPE1 regulated GPX4 to affect cell lipid peroxidation levels and GSH accumulation. HSPE1 plays a crucial role in regulating GPX4 to prevent BLCA cells from undergoing ferroptosis, with this control mechanism dependent on GSH.

The Sophora alopecuroide - Taraxacum Decoction (STD) is a traditional Chinese herbal formulation that has demonstrated significant potential in combating tumors. Despite its apparent effectiveness, the specific mechanisms through which STD exerts its anti-tumor properties remain largely unexplored and are yet to be fully understood. In our study, we provided evidence that STD effectively inhibits cellular growth and movement, as well as halting the cell cycle at the G2/M checkpoint. Furthermore, our pharmacological network analysis indicated that STD might induce cell death through a process known as ferroptosis. This hypothesis was substantiated by observing important biochemical changes associated with ferroptosis, including a decrease in glutathione (GSH) levels, an increase in iron accumulation, and elevated levels of reactive oxygen species (ROS) and lipid peroxidation. Additionally, we noted a significant rise in the expression of pro-ferroptosis genes such as Keap1, Nrf2, and HO-1, further supporting our findings. Significantly, and in line with the in vitro results, STD also showed a strong ability to inhibit tumor growth by inducing ferroptosis in a subcutaneous tumor model. Additionally, STD treatment changed the tumor immune microenvironment (TIME), as seen by an increase in CD107a+ CD8 and NK cells within the tumor. These findings demonstrate that STD induces ferroptosis and alters TIME to combat tumors, suggesting that STD may be a viable alternative treatment for patients with NSCLC.

Lung cancer (LC) is the leading cause of cancer-related deaths and the second most commonly diagnosed malignancy worldwide. Lung adenocarcinoma (LUAD) and lung squamous cell LC (LUSCC) are the most common subtypes of non-small cell LC (NSCLC). Early diagnosis of LC can be challenging due to a lack of biomarkers. The overall survival (OS) of patients with NSCLC is still poor despite the enormous efforts that have been made to develop novel treatments. Understanding fundamental molecular and genetic mechanisms is necessary to develop new therapeutic approaches for NSCLC. A recently identified type of programmed cell death known as ferroptosis is one potential approach. Ferroptosis causes oxidative damage and the death of cancerous cells by peroxidizing unsaturated phospholipids and accumulating reactive oxygen species (ROS) in an iron-dependent manner. Ferroptosis-related gene (FRG) signatures have recently been evaluated for their ability to predict patient OS and prognosis. These analyses show FRGs are involved in cancer progression, and may serve as promising biomarkers for tumor diagnosis and therapy. Moreover, we summarize the current pharmaceutical options of ferroptosis induction and their underlying molecular mechanism in LC. Therefore, this review aims to provide a comprehensive summary of FRG-based prognostic models, their associated metabolic and signaling pathways, and promising therapeutic options for ferroptosis induction in NSCLC.

Ferroptosis plays a crucial role in the progression of postmenopausal osteoporosis. Anemarrhena asphodeloides Bunge/Phellodendron chinense C.K. Schneid (AA/PC) is the core herb pair in traditional Chinese medicines formulae for postmenopausal osteoporosis treatment. However, the synergistic effects, and mechanisms, of AA/PC on alleviating ferroptosis and postmenopausal osteoporosis remain unclear.

The goal herein was to analyze the effective ingredients and molecular mechanisms of AA/PC in the treatment of osteoporosis through serum pharmacochemistry, network pharmacology, metabolomics analysis, and pharmacodynamics evaluation. A bilateral ovariectomized (OVX) mouse model was established.

Micron-scale computed tomography analysis showed that AA/PC increased bone mineral density in OVX mice. The effects of AA/PC were better than AA or PC alone on inhibiting the bone resorption marker nuclear factor of activated T-cells 1. Furthermore, five absorbable compounds were detected in serum: mangiferin, magnoflorine, berberine, timosaponin BIII, and timosaponin AIII. Network pharmacology showed these compounds had close relationship with seven ferroptosis targets. Importantly, compared with AA or PC alone, the AA/PC herb pair exerted better effects on regulating crucial ferroptosis pathways, including the system xc-/glutathione/glutathione peroxidase 4, transferrin receptor/ferritin, and acyl-CoA synthetase long chain family member 4/polyunsaturated fatty acids signaling pathways. These results indicate that AA/PC exerts synergistic effects on regulating glutathione synthesis, iron homeostasis, and lipid metabolism in ferroptosis. This work lays the foundation for further development and use of AA/PC herb pair for preventing and treating postmenopausal osteoporosis.

Isoquercitrin possesses anti-tumor activity in several types of cancers, however, its effects and underlying mechanisms on lung cancer have not been reported. Human lung cancer cell lines as well as normal lung epithelial BEAS-2B cells were treated with isoquercitrin. The influences of isoquercitrin in vitro were evaluated by determining cell viability, apoptosis, pyroptosis, and ferroptosis. Additionally, A549 tumor-bearing mice were generated to explore the anti-cancer effect of isoquercitrin in vivo. We found that isoquercitrin dose-dependently reduced lung cancer cells' viability, with no toxicity against BEAS-2B cells. Isoquercitrin at 40 μM and 80 μM was used in vitro. Isoquercitrin increased apoptosis, elevated NLRP3 inflammasome activation-mediated pyroptosis, and promoted ferroptosis in lung cancer cells. NLRP3 knockdown and caspase-1 selective inhibitor VX-765 attenuated isoquercitrin-induced pyroptosis and ferroptosis, but not apoptosis. Furthermore, isoquercitrin accelerated ROS generation, while ROS inhibitor N-acetylcysteine abrogated isoquercitrin-induced apoptosis, NLRP3 related-pyroptosis and ferroptosis. In vivo, isoquercitrin (1 mg/kg and 5 mg/kg) inhibited tumor growth, increased apoptosis, NLRP3-related pyroptosis, ferroptosis and ROS generation in tumors. Taken together, isoquercitrin inhibits lung cancer growth by triggering ROS/NLRP3-mediated pyroptosis and ferroptosis, with ROS also directly inducing apoptosis. This suggests that isoquercitrin might be a potential therapeutic agent for lung cancer.

Ferroptosis, a non-apoptotic form of regulated cell death, plays a critical role in the suppression of various tumor types, including ovarian cancer. Artesunate (ART), a derivative of artemisinin, exhibits extensive antitumor effects and is associated with ferroptosis. This study aimed to investigate the mechanisms through which ART induces ferroptosis to inhibit ovarian cancer.

RNA sequencing was conducted to identify differentially expressed genes associated with ART-induced ferroptosis. Dual-luciferase reporter assays and electrophoretic mobility shift assays were performed to confirm the interaction between Homeobox C11 (HOXC11) and the Prominin 2 (PROM2) promoter. Cell Counting Kit-8 (CCK-8) assays, flow cytometry, and wound healing assays were used to analyze the antitumor effects of ART. Western blot, biochemical assays and transmission electron microscope were utilized to further characterize ART-induced ferroptosis. In vivo, the effects of ART on ferroptosis were examined using a xenograft mouse model.

RNA sequencing analysis revealed that the HOXC11, PROM2 and Phosphatidylinositol 3-Kinase/ Protein Kinase B (PI3K/AKT) pathways were downregulated by ART. HOXC11 was found to regulate PROM2 expression by binding to its promoter directly. HOXC11 overexpression reversed ART-induced effects on ovarian cancer cell proliferation, migration, apoptosis and ferroptosis by activating the PROM2/PI3K/AKT signaling axis. Conversely, silencing PROM2 in HOXC11-overexpressing cells restored ART-induced ferroptosis and its associated antitumor effects by inhibiting the PI3K/AKT pathway. Consistently, in vivo studies using a xenograft mouse model confirmed that ART-induced tumor inhibition was mediated by ferroptosis through the suppression of the HOXC11/PROM2/PI3K/AKT pathway.

This study identifies the HOXC11/PROM2/PI3K/AKT axis as a novel regulatory mechanism underlying ART-induced ferroptosis in ovarian cancer. Targeting the HOXC11/PROM2 axis may represent a promising therapeutic strategy for enhancing ferroptosis, offering new insights for the treatment of ovarian cancer.

Doxorubicin (DOX) is an anthracycline that has excellent anticancer effects during tumor chemotherapy, but it can cause cardiotoxic effects and its clinical use has been limited. Therefore, finding new drugs or methods to prevent or reverse the cardiac damage caused by DOX therapy in cancer patients is essential. Previous studies have identified potential cardioprotective effects of Centella asiatica (C. asiatica), and madecassic acid (MA) is a pentacyclic triterpenoid derived from C. asiatica. However, the pharmacological effects of MA on the heart and tumors during tumor chemotherapy are not fully understood. The aim of this study was to investigate the pharmacological function and molecular mechanisms of MA in the heart and tumor during chemotherapy. In a DOX-induced acute heart failure mouse model and a cardiomyocyte injury model, MA reduced cardiomyocyte oxidative stress and the inflammatory response, improved mitochondrial function, and attenuated autophagic flux blockade and apoptosis. Interestingly, MA significantly increased the expression and activity of SIRT1. When SIRT1 was knocked down, the protective effect of MA on cardiomyocytes was significantly inhibited, suggesting that MA may exert cardioprotective effects through the SIRT1 pathway. Interestingly, in contrast to its cardioprotective effect, MA could synergize with DOX and significantly contribute to the anticancer chemotherapeutic effect of DOX by inhibiting proliferation, migration and invasion; promoting apoptosis; and suppressing tumor progression by inhibiting the expression of the DDX5 pathway in tumor cells. Here, we identified the pharmacological functions of the pentacyclic triterpenoid MA in ameliorating DOX-induced cardiotoxicity and enhancing the antitumor efficacy of DOX.

As a common malignancy, lung cancer has a relatively poor prognosis and a low survival rate. In recent years, ferroptosis, as an emerging filed, has great promise in the potential treatment of cancer. Brucea javanica oil (BJO) is often used to treat various cancers. Oleic acid (OA) is the main ingredient of BJO. In this study, we investigated the role and molecular mechanism of OA in lung cancer treatment by promoting ferroptosis.

In this study, A549 cells and H1299 cells were used for in vitro experiments, and a CCK-8 test, scratch test, and MTT experiment were carried out. We examined reactive oxygen species (ROS), the JC-1 probe, glutathione (GSH) expression, lipid peroxidation, SDC4 mRNA levels, and ACSL4, SLC7A11, GPX4, and SDC4 protein levels.

The results showed that OA could inhibit the proliferation and migration of A549 cells and H1299 cells, SDC4 was a potential therapeutic target of OA against lung cancer, and OA treatment significantly inhibited the expression of SDC4 in A549 cells and H1299 cells. OA induces ferroptosis in A549 cells and H1299 cells, decreases GSH levels, increases lipid peroxidation levels, and decreases SDC4 mRNA expression; in addition, OA upregulates ACSL4 expression and decreases SLC7A11, GPX4, and SDC4 expression.

This study confirmed that OA could inhibit SDC4 expression and promote the occurrence of ferroptosis in A549 cells and H1299 cells through the GPX4/ACSL4 pathway, providing an effective basis for the use of drugs targeting ferroptosis in lung cancer treatment.