Primary liver cancer (PLC) is among the most common malignant tumors of the digestive tract, with high incidence and mortality. Hepatocellular carcinoma (HCC) the predominant PLC form has complex pathogenesis. Traditional Chinese medicine (TCM) has gained widespread use as supportive treatment, demonstrating clear efficacy in HCC management. This article summarizes signaling pathways regulating ferroptosis in HCC cells and systematically reviews current research on pathway modulation by TCM active constituents and compound formulas, emphasizing their cytotoxic effects. HCC cellular survival strategies that evade ferroptosis, including hepatic stellate cell-mediated protective mechanisms, are discussed. Clinical limitations of ferroptosis-based treatments and potential solutions are addressed. A comprehensive literature search using PubMed, Embase, Web of Science, and Scopus examined signaling pathways in TCM-mediated ferroptosis in HCC cells. Search terms included "hepatocellular carcinoma," "ferroptosis," "signaling pathway," "traditional Chinese medicine," "TCM monomer," "TCM formula," and "TCM extract," limited to studies from January 2021 to October 2025. Thirty-nine studies were identified: 33 on TCM active ingredients, 1 on TCM extract, and 5 on herbal formulas. TCM active ingredients and formulas promote ferroptosis in HCC cells through modulation of signaling pathways. Pathway modulation inhibits HCC cell proliferation, invasion, and metastasis; promotes apoptosis; increases chemotherapeutic sensitivity; improves glucose metabolism; and reduces drug resistance. TCM can induce ferroptosis in HCC cells through multiple pathways, targets, and mechanisms,highlighting its therapeutic advantages and providing guidance for developing novel ferroptosis inducers.

Epimedium polysaccharide alleviates adenine-induced oligoasthenozoospermia in mice by inhibiting ferroptosis and inflammation through TLR4/NF-κB and SLC7A11/GPX4 axis.

To investigate the mechanism by which BRD4 accelerates acute lung injury (ALI) by promoting ferroptosis mediated by ANP32B/H3K27ac/MYC/HOXB8/BACH1 in alveolar epithelial cells. Gene co-expression was analyzed with bioinformatics. Eighteen SPF-grade C57BL/6J male mice (6-8 weeks old, 20 ± 4 g) were divided into three groups: Sham, Model, and Model-JQ1. Lung function was analyzed post-anesthesia; after euthanasia, lung tissues were collected for TEM to observe structural changes. HE staining assessed cellular morphology and pathology, while Prussian blue staining evaluated iron deposition. Western Blot detected BRD4, ANP32B, MYC, HOXB8, and BACH1 protein expression. ELISA measured GSH, MDA, lipid ROS, Fe2+, and LPO levels. MLE-12 cells were cultured and divided into four groups: NC, LPS, LPS-JQ1, and LPS-JQ1-BACH1-OE. Western Blot and immunofluorescence analyzed protein expression, and TEM observed cell ultrastructure. ELISA assessed oxidative stress markers. HOXB8 regulates BACH1, impacting oxidative stress and iron metabolism genes. LPS induced significant cell damage, alleviated by BRD4 inhibition. JQ1 improved lung injury and function, reduced iron accumulation, and oxidative damage. Western Blot and ELISA showed LPS upregulated key proteins, reversed by BRD4 inhibition. JQ1 inhibited LPS-induced stress in cells; BACH1 overexpression partially reversed this. Immunofluorescence showed BRD4 inhibition suppressed BACH1 and promoted SLC7A11 expression. ALI is accelerated by BRD4 through the promotion of ANP32B/H3K27ac/MYC/HOXB8/BACH1-mediated ferroptosis in alveolar epithelial cells. A deeper understanding of the role of BRD4 in alveolar epithelial cell injury is provided by these findings, and potential therapeutic targets for the treatment of ALI may be identified.

Methodological approaches for dissecting ferroptosis in lens epithelial cells and its role in diabetic cataract progression.

Epigallocatechin gallate alleviates intervertebral disc degeneration by suppressing ferroptosis-driven innate immune activation in nucleus pulposus cells.

Andrographolide induces testicular damage by triggering ferroptosis in Sertoli cells via disruption of β-TrCP-mediated ATF4 ubiquitination and degradation.

ZFP36 inhibits trophoblast ferroptosis and attenuates preeclampsia development by promoting NCOA4 mRNA degradation and suppressing ferritinophagy.

Synergistic induction of ferroptosis by paclitaxel and sunitinib is mediated through SLC7A11 in lung cancer.

Long-acting multiple programmed cell death nanoinducers based on polyunsaturated fatty acid supplemented liposomal photosensitizers for enhanced photodynamic immunotherapy.

Pien Tze Huang ameliorates alcohol-associated liver disease via suppressing oxidative stress and ferroptosis.

Polystyrene nanoplastics disrupt iron homeostasis by promoting FPN1 ubiquitination in GC-2spd(ts) cells.

Glycolysis inhibition-based breakdown of ferroptosis defenses to achieve ferroptosis and immune cascades for antitumor therapy.

Sodium aescinate induces renal cell ferroptosis through the ATF4/CTH/SQOR axis.

Asthma is characterized by persistent airway inflammation, and ferroptosis is closely related to this pathological manifestation. Although studies have explored the inducing factors of asthmatic inflammation, the regulatory mechanisms during the resolution phase and the role of ferroptosis in it remain unclear. In this study, proteomics was performed to characterize functional alterations in intrapulmonary airway epithelial cells during the resolution phase in an ovalbumin (OVA)-induced inflammation mouse model. The correlations among DECR1, ferroptosis, and airway inflammation were analyzed. The effects of DECR1 knockdown on ferroptosis and epithelial function, and the regulatory mechanism were examined invitro. The impact of recombinant DECR1 administration and adeno-associated virus (AAV)-mediated DECR1 overexpression on inflammation resolution was evaluated invivo. Finally, DECR1 levels in asthma patients were measured and correlated with clinical parameters. We demonstrated that the proteome underwent significant changes during the inflammation resolution phase in mice with OVA-induced airway inflammation, with DECR1 showing a marked decrease at the peak of inflammation and recovered during resolution. DECR1 levels were negatively correlated with airway inflammation and ferroptosis-associated markers. Invitro, our results confirmed that DECR1 deficiency induced ferroptosis and disrupted epithelial function by upregulating DUOXA1. Invivo, recombinant DECR1 administration or AAV-mediated DECR1 overexpression alleviated airway inflammation and accelerated resolution through mediating epithelial ferroptosis. Consistently, DECR1 levels were also reduced in asthma patients and positively correlated with lung function. Together, DECR1 regulates epithelial ferroptosis through DUOXA1-dependent mechanisms, thereby preserving epithelial integrity and promoting inflammation resolution. Targeting DECR1 may offer a novel therapeutic strategy for asthma.

Objective: To investigate the mechanism through which timosaponin AⅢ (TAⅢ)-based liposomes loaded with auranofin (AUF) (T-AUF-LPs) induce ferroptosis in anaplastic thyroid carcinoma cells. Methods: T-AUF-LPs were prepared using the thin-film hydration method, and their physicochemical properties and stability were characterized. Additionally, conventional liposomes (C-AUF-Lips) were prepared using cholesterol as the membrane material. Cellular uptake efficiency was evaluated in CAL-62 cells using coumarin-6-labeled liposomes. Cell viability was assessed via CCK-8 assay. The role of ferroptosis was confirmed using the inhibitor Ferrostatin-1 (Fer-1) and flow cytometric analysis of cell death. The expression of ferroptosis-related markers (ACSL4, NCOA4, GPX4) were detected using RT-qPCR and Western blot. Levels of intracellular iron, glutathione (GSH), and lipid peroxidation were measured. A nude mouse tumor xenograft model was established to evaluate the in vivo antitumor efficacy of T-AUF-LPs, and hematoxylin-eosin (HE) staining was performed to assess potential systemic toxicity. Results: T-AUF-LPs appeared as uniformly distributed spherical particles with an average size of (119.40±3.11) nm, which was significantly smaller than that of the conventional liposomes C-AUF-LPs (P＜0.001). The zeta potential of T-AUF-LPs was (-12.07±0.65) mV, lower than that of C-AUF-LPs (P=0.002). Furthermore, CAL-62 cells exhibited significantly enhanced cellular uptake of T-AUF-LPs compared to C-AUF-LPs. Cell experiments demonstrated that among the established groups, i.e., Control, TAⅢ, AUF, AUF+TAⅢ, C-AUF-LPs, and T-AUF-LPs, the T-AUF-LPs group exhibited the lowest half-maximal inhibitory concentration (IC50=0.66 μmol/L) and the highest CAL-62 cell mortality (14.7±1.3)%. Furthermore, this group showed significantly elevated lipid peroxidation (2.07±0.28), increased iron content (4.64±0.17), and markedly reduced glutathione (GSH) levels (0.11±0.05). At the molecular level, mRNA expression of ACSL4 and NCOA4 was up-regulated (13.10±0.94 and 7.52±0.49, respectively), while GPX4 mRNA was down-regulated (0.16±0.21). Consistently, ACSL4 and NCOA4 protein expression was increased (1.30±0.06 and 1.13±0.31, respectively), whereas GPX4 protein expression was decreased (0.31±0.18).Notably, pretreatment with the ferroptosis inhibitor Fer-1 significantly reversed T-AUF-LPs-induced cell death, reducing mortality to (8.8±0.8)%. Animal studies demonstrated that among all groups, tumor growth was most significantly suppressed in the T-AUF-LPs group, which exhibited the smallest tumor volume on day 15 post-inoculation. No significant body weight loss was observed in nude mice, and histopathological assessment of the heart, liver, lungs, and kidneys revealed no apparent toxic damage. In tumor tissues of the T-AUF-LPs group, mRNA expression of ACSL4 and NCOA4 was significantly up-regulated (1.59±0.29 and 8.65±3.48, respectively), while GPX4 mRNA expression was markedly down-regulated (0.11±0.01). Consistently, ACSL4 and NCOA4 protein levels were increased (1.26±0.31 and 1.14±0.39, respectively), whereas GPX4 protein expression was significantly reduced (0.56±0.12). Conclusion: T-AUF-LPs inhibited the growth of anaplastic thyroid carcinoma cells by activating the ferroptosis pathway.

This study explores the molecular mechanism of HDAC5 in ferroptosis of intestinal epithelial cells in sepsis-induced acute intestinal injury. A mouse model was established by cecal ligation and perforation (CLP) and an in vitro model of intestinal epithelial cells was induced by lipopolysaccharide (LPS). Immunohistochemistry, RT-qPCR, or Western blot determined the expressions of HDAC5, KLF4, and LncRNA MEG3 in cells. HDAC5 expression was reduced via lentivirus injection and siRNA transfection, followed by evaluation of intestinal tissue injury and cell injury, detection of Fe2+, ROS, GSH, and MDA levels, as well as detection of ACSL4 and SLC7A11 protein expressions. The permeability was evaluated by detecting the flux of fluorescein isothiocyanate-dextran. ChIP analyzed the enrichment of HDAC5 and H3K27ac on KLF4 promoter. The binding of KLF4 to LncRNA MEG3 promoter was verified by ChIP and dual luciferase assays. RIP and RNA pull down analyzed the binding of LncRNA MEG3 to LSD1. The enrichment of LSD1, H3K4me2, or H3K9me2 on ACSL4 or SLC7A11 promoter was analyzed by ChIP. HDAC5 expression was increased in intestinal tissues of CLP mice and LPS-induced cells, while KLF4 and LncRNA MEG3 expressions were decreased. Low expression of HDAC5 alleviated intestinal tissue injury, enhanced LPS-induced cell viability, and reduced ferroptosis. Mechanistically, HDAC5 inhibited KLF4 expression through deacetylation of H3K27ac, thereby suppressing transcriptional promotion of LncRNA MEG3 by KLF4, reducing recruitment of LSD1, enhancing H3K4me2 on ACSL4 promoter and H3K9me2 enrichment on SLC7A11 promoter, promoting ACSL4 and inhibiting SLC7A11 expression. HDAC5 promotes intestinal epithelial cell ferroptosis and exacerbates sepsis-induced acute intestinal injury by inhibiting KLF4/LncRNA MEG3 axis through deacetylation of H3K27ac.

The ferroptosis of intestinal epithelial cells (IECs), an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a critical pathogenic driver of ulcerative colitis (UC). This review summarizes the core hallmarks of IEC ferroptosis in UC-specifically, lipid peroxidation, iron overload, and antioxidant system dysregulation-and describes key regulatory signaling networks, including the Nrf2/HO-1, SLC7A11/GPX4, and AMPK/mTOR pathways. Furthermore, we systematically evaluated emerging therapeutic strategies targeting these mechanisms, categorized into antioxidant activation, iron and lipid metabolism regulation, immune and microbiota modulation, and multitarget interventions. Elucidating this complex ferroptotic regulatory network provides a vital theoretical foundation for the development of novel disease-stage-specific therapeutic paradigms for UC management.

USP1 represses ferroptosis in endometrial carcinoma cells by regulating the ubiquitination and stability of ESR1.

Nasopharyngeal carcinoma (NPC) is a highly prevalent malignant epithelial tumor in southern China. Although early-stage NPC patients have a favorable prognosis with concurrent chemoradiotherapy, the limited efficacy of current clinical regimens remains a crucial obstacle in the treatment of advanced NPC patients. 5-Methoxyflavone, a methylated flavonoid, has been reported to exhibit diverse roles in anti-cancer activity and lipid modulation. However, its potential role in NPC remains unclear. This study aims to investigate the effect of 5-Methoxyflavone on NPC proliferation and its underlying mechanism. MTT, colony formation, EdU assays, and flow cytometry were performed with various concentrations of 5-Methoxyflavone (0, 40, 60, 80 and 100 µM) to investigate its effect on NPC cell proliferation. A HONE1 xenograft model was established for in vivo validation. Immunoprecipitation and dual-luciferase reporter assay were employed to confirm 5-Methoxyflavone's regulatory function on the p53/SREBPs pathway. Lipid synthesis was determined by measuring total cholesterol and triglycerides using ELISA and visualizing lipid droplets via Oil Red O staining. Ferroptosis was evaluated by detecting intracellular ferrous ions, lipid ROS, and glutathione (GSH) levels. 5-Methoxyflavone suppressed NPC cell proliferation in a concentration-dependent manner in vitro. In addition, it profoundly inhibited tumor xenograft growth in mice without causing obvious adverse toxicity. Mechanistically, 5-Methoxyflavone deubiquitinated and stabilized p53 via inhibiting MDM2 expression, leading to suppression of SREBPs and their downstream lipid synthesis-related genes, thus inhibiting lipid synthesis in NPC cells. p53 depletion counteracted 5-Methoxyflavone's inhibitory effect, while SREBP1 knockdown restored proliferation in p53-silenced cells. Furthermore, 5-Methoxyflavone-stimulated downregulation of SREBP1/SCD signaling triggered ferroptosis in NPC cells by promoting iron accumulation, lipid peroxidation, and GSH depletion. Overexpression of SCD reversed the ferroptosis-inducing effects of 5-Methoxyflavone. Our findings reveal that 5-Methoxyflavone inhibits NPC proliferation by blocking lipid synthesis and inducing ferroptosis via the p53/SREBPs/SCD signaling pathway, providing evidence for the development of innovative drugs for NPC treatment.

Ovarian cancer is the most prevalent and deadly gynecological malignancy worldwide, with a 5-year overall survival rate of only 10%-40% for patients with advanced disease. Copper chaperone for superoxide dismutase 1 (CCS) is a metallochaperone that plays a multifaceted role in the maturation of copper and displays aberrant expression levels and functions in cancer. Ferroptosis, a new form of cell death resulting from iron-dependent lipid peroxidation, is closely related to cancer. However, whether CCS regulates ferroptosis in ovarian cancer is unknown, and its underlying mechanisms have not been reported. Here, we report that highly expressed CCS contributes to ovarian cancer tumor growth. Moreover, suppressing CCS induced ferroptosis in ovarian cancer cells and increased their sensitivity to ferroptosis inducers. Mechanistically, high CCS expression was found to reduce intracellular copper ion levels and increase Solute Carrier Family 7 Member 11 (SLC7A11) or Glutathione Peroxidase 4 (GPX4) expression by increasing p53 ubiquitination, thus affecting ferroptosis. Additionally, DC_AC50, a small-molecule inhibitor of CCS that targets its copper transport interface, regulates ferroptosis and ovarian cancer growth. Analysis of clinical data revealed a positive correlation between high CCS expression and high SLC7A11 and GPX4 expression in ovarian cancer patients. In summary, our study reveals that CCS protects ovarian cancer cells from ferroptosis by promoting SLC7A11 and GPX4 expression in a p53-dependent manner.