Gut microbiota exerts a pivotal influence on the development of Metabolic Associated Fatty Liver Disease (MAFLD), although the specific contributions of individual bacterial strains and their metabolites remain poorly defined. We conducted stool shotgun metagenomic sequencing and plasma untargeted metabolomics in a large prospective cohort comprising 120 MAFLD patients and 120 matched healthy controls. The mechanisms and microbial-derived metabolites involved in MAFLD were further investigated through multi-omics analyses in vitro and in vivo. Distinct differences were identified in both the microbial community structure and metabolomic profiles between MAFLD patients and healthy controls. Bacteroides uniformis (B. uniformis) was the most significantly depleted species in MAFLD and negatively correlated with hepatic steatosis and BMI. MAFLD was characterized by marked disruptions in fatty acid and amino acid metabolism. Combined analysis of metabolomic and metagenomic data achieved high diagnostic accuracy for MAFLD and hepatic steatosis severity (AUC = 0.93). Transplantation of fecal microbiota from MAFLD subjects into ABX mice led to the onset of MAFLD-like symptoms, whereas B. uniformis administration alleviate disease progression by inhibiting intestinal fat absorption, FFA from eWAT influx into liver via the gut-liver axis, and IRE1α-XBP1s-mediated flipogenesis and ferroptosis, as confirmed by hepatic transcriptomic and proteomic analyses. Hexadecanedioic acid (HDA), potentially identified as a key metabolite produced by B. uniformis, ameliorated MAFLD symptoms. Mechanistically, B. uniformis-derived HDA also inhibited fat absorption and transported, and entered the liver via the portal vein to suppress IRE1α-XBP1s-mediated flipogenesis and ferroptosis. B. uniformis and its potential putative metabolite HDA may contribute to MAFLD progression modulation, through regulation of the IRE1α-XBP1s axis. This study provides new insights into the gut-liver axis in MAFLD and offers promising therapeutic targets based on specific microbes and their metabolites.

The current study aims to identify the key pathways and potential therapeutic targets for pulmonary arterial hypertension (PAH) and to further evaluate the anti-PAH effects of isorhamnetin.

The dataset of gene expression profiling for PAH (GSE113439) was downloaded from the gene expression omnibus (GEO) database. Isorhamnetin target genes were extracted from the comparative toxicogenomics database (CTD). Various bioinformatics methods were employed to identify the core pathways associated with PAH and potential intervention targets. Molecular docking was conducted between the interacting target and the candidate compound, isorhamnetin.

One thousand nine hundred sixty-two upregulated genes and 642 downregulated genes were identified. Molecular complex detection analyses revealed that the significant biological processes associated with upregulated genes included DNA damage response, mitotic cell cycle, and chromosome organization. In contrast, the signifi ant biological processes related to downregulated genes encompassed cellular response to growth factor stimulus, response to growth factor, and blood vessel development. Immune infilt ation analysis indicated that PAH is associated with signifi ant changes in the distribution of immune cells and differential expression of immune checkpoints. Furthermore, 58 isorhamnetin targets were extracted from the CTD, and we identified 1 interacting gene, NFE2L2, among the differentially expressed genes (DEGs), DEGs related to ferroptosis, and isorhamnetin targets. Isorhamnetin demonstrated strong affinities with vascular endothelial growth factor (VEGF) receptors and transcription factors (ATM and ZNF24) associated with VEGFs, as well as the ferroptosis protein NFE2L2.

Pulmonary arterial hypertension is characterized by a series of abnormalities in downstream molecular signaling pathways, including DNA damage, immune dysregulation, VEGF signaling deficienc , and the ferroptosis process. These may represent the core pathophysiological mechanisms of PAH. Ferroptosis-related genes, such as NFE2L2 and TF (ATM, ZNF24) associated with VEGFs, are potential therapeutic targets that contribute to the mechanisms mentioned above. Isorhamnetin is a promising candidate compound for the treatment of PAH.

Epithelial-mesenchymal transition (EMT) is a cellular de-differentiation process that provides cells with the increased plasticity and stem cell-like traits required during embryonic development, tissue remodeling, wound healing and metastasis. Morphologically, EMT confers tumor cells with fibroblast-like properties that lead to the rearrangement of cytoskeleton (loss of stiffness) and decrease of membrane rigidity by incorporating high level of poly-unsaturated fatty acids (PUFA) in their phospholipid membrane. Although large amounts of PUFA in membrane reduces rigidity and offers capabilities for tumor cells with the unbridled ability to stretch, bend and twist in metastasis, these PUFA are highly susceptible to lipid peroxidation, which leads to the breakdown of membrane integrity and, ultimately results in ferroptosis. To escape the ferroptotic risk, EMT also triggers the rewiring of metabolic program, particularly in lipid metabolism, to enforce the epigenetic regulation of EMT and mitigate the potential damages from ferroptosis. Thus, the interplay among EMT, lipid metabolism, and ferroptosis highlights a new layer of intricated regulation in cancer biology and metastasis. Here we summarize the latest findings and discuss these mutual interactions. Finally, we provide perspectives of how these interplays contribute to cellular plasticity and ferroptosis resistance in metastatic tumor cells that can be explored for innovative therapeutic interventions.

Methionine sulfoxide reductase A (MsrA) is an important antioxidant enzyme that is present in various tissues and play a crucial role in many pathological processes. However, the role of MsrA in acute kidney injury (AKI) requires further exploration. Here, we aimed to explore whether MsrA is involved in sepsis-associated AKI and the underlying mechanisms. In the present study, AKI was induced by lipopolysaccharide (LPS) in WT mice and MsrA knockout mice. The role of MsrA in LPS-induced injury in the human renal proximal tubule epithelial cell line HK-2 was also examined by MsrA knockdown. MsrA deficiency exacerbated LPS-induced kidney damage in vivo. In addition, MsrA deficiency and silencing intensified iron overload, lipid peroxidation and ferroptosis in LPS-stimulated renal tubular cells. The mechanistic study revealed that MsrA knockout or knockdown led to the oxidation of calcium/calmodulin-dependent protein kinase II (CaMKII) at methionine 281/282, resulting in sustained activation of CaMKII, which upregulated iron metabolism-related proteins such as transferrin receptor 1 (TFR1) by promoting phosphorylation and nuclear translocation of hypoxia-inducible factor-1α (HIF-1α) and induced abnormal iron metabolism. Meanwhile, CaMKII activation downregulated the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) by inhibiting the activity of AMP-activated protein kinase (AMPK) and phosphorylation of nuclear factor erythroid 2-related factor 2 (NRF2), resulting in lipid peroxidation. Consequently, LPS-induced ferroptosis was exacerbated. Our study is the first to reveal that MsrA deficiency intensifies LPS-induced ferroptosis through CaMKII activation in renal tubular cells. There are two major mechanisms: one is the promotion of lipid peroxidation by inhibiting the AMPK/NRF2 axis, and the other is abnormal iron metabolism by activating the HIF-1α/TFR1 pathway. MsrA may be a potential therapeutic target for organ and cell damage induced by ferroptosis.

Ferroptosis is a form of regulated cell death characterized by iron accumulation and increased lipid peroxidation, primarily counteracted by a range of antioxidant molecules, including glutathione (GSH), glutathione peroxidase 4 (GPX4), ubiquinone, tetrahydrofolate, and nuclear respiratory factor 2. Furthermore, the process of ferroptosis is intricately influenced by the opposing actions of the p53 tumor suppressor gene and activated transcription factors 3 and 4, which can either facilitate or hinder ferroptotic cell death depending on the cellular context. This form of cell death is significantly associated with various pancreatic disorders, including both acute and chronic pancreatitis, as well as diabetes mellitus. In this review, we thoroughly investigate the mechanisms underlying ferroptosis, focusing on iron overload, lipid peroxidation, and the regulatory molecules involved in ferroptosis modulation (notably the system xc-/GSH/GPX4 axis), along with the relevant signaling pathways. We also examine the role of ferroptosis in non-neoplastic pancreatic diseases such as pancreatitis and diabetes mellitus while identifying novel therapeutic agents that target ferroptosis, potentially paving the way for innovative treatment strategies for pancreatic conditions.

The mechanisms underlying the negative health effects of microwave exposure on male reproduction remain unclear. Thus, this study aimed to explore the role and regulatory mechanisms of ferroptosis in microwave-induced reproductive damage. The exposure of male C57 mice to 2.856 GHz of microwave radiation at 0, 10 and 20 mW/cm² for 30 min decreased sperm motility, induced morphological changes, damaged testicular tissue and mitochondrial morphology, increased malondialdehyde (MDA) contents and decreased the GSH/GSSG ratio. Simultaneously, the Fe²⁺ levels increased and SLC7A11 and GPX4 protein expressions decreased, causing oxidative stress. After 30 min of mouse spermatocyte (GC-2) irradiation, the cell viability of the Fer-1 inhibitor group and the GSH/GSSG ratio increased, while the reactive oxygen species, MDA and ferrous iron contents decreased. Furthermore, the depolarisation of membrane potential improved. Western blotting revealed that Nrf2, Keap1, SLC7A11, GPX4 and HO-1 expressions were down-regulated by microwave exposure and significantly up-regulated following the addition of the Fer-1 inhibitor. The results confirmed that the Nrf2 signalling pathway can regulate ferroptosis of oxidative stress. This study demonstrates that microwave exposure affects mouse reproductive function by enhancing oxidative stress, inducing ferroptosis by inhibiting the Nrf2 signalling pathway and reducing SLC7A11 and GPX4 protein expressions.

Kidney disease (KD) has gradually become a major social and economic burden on the healthcare system. Recent studies highlight ferroptosis as a critical mechanism in the progression of these conditions. Recognized for its essential role in renal pathogenesis, ferroptosis is attracting increasing research attention and emerging as a key focus of investigation. The Nrf2 signaling pathway, known for its regulatory influence on ferroptosis, plays a central role in this context. Activation of the nuclear factor E2-related factor 2 (Nrf2) pathway and the subsequent attenuation of ferroptosis present substantial opportunities as novel therapeutic targets for managing kidney injury (KI). This article summarizes the latest mechanism of action of the Nrf2 pathway in ferroptosis, explores how the Nrf2 pathway affects ferroptosis in KD therapy, and investigates the potential therapeutic effects of natural products targeting the Nrf2 pathway. These natural products have been shown to inhibit ferroptosis through the Nrf2 pathway, providing new insights and therapeutic strategies for the clinical and individualized management of KD.

Chemoresistance poses a significant challenge in colorectal cancer (CRC) treatment. However, the mechanisms underlying chemoresistance remain unclear. CBX3 promoted proliferation and metastasis in CRC. However, the role and mechanism of CBX3 in chemoresistance remain unknown. Therefore, we aimed to investigate the effects and mechanisms of CBX3 on multidrug resistance in CRC. Our studies showed that higher levels of CBX3 expression were associated with poor survival, especially in groups with progression following chemotherapy. CBX3 overexpression increased Irinotecan and Oxaliplatin resistance, whereas CBX3 knockdown suppressed multidrug resistance in CRC cells. Additionally, CBX3 inhibited ferroptosis associated with multidrug resistance, and the ferroptosis activators prevented CBX3 overexpression-mediated cell survival. RNA sequencing revealed that the NRF2-signaling pathway was involved in this process. CBX3-upregulated NRF2 protein expression by directly binding to the promoter of Cullin3 (CUL3) to suppress CUL3 transcription and CUL3-mediated NRF2 degradation. Moreover, Glutathione Peroxidase 2 (GPX2) was downstream of the CBX3-NRF2 pathway in CRC chemoresistance. ML385, an NRF2 inhibitor, suppressed GPX2 expression, and increased ferroptosis in PDX models. Our study identified CBX3/NRF2/GPX2 axis may be a novel signaling pathway that mediates multidrug resistance in CRC. This study proposes developing novel strategies for cancer treatment to overcome drug resistance in the future.

Oxygen and sulfur, both members of the chalcogen group (group 16 elements), play fundamental roles in life. Ancient organisms primarily utilized sulfur for energy metabolism, while the rise in atmospheric oxygen facilitated the evolution of aerobic organisms, enabling highly efficient energy production. Nevertheless, all modern organisms, both aerobes and anaerobes, must protect themselves from oxygen toxicity. Interestingly, aerobes still rely on sulfur for survival. This dependence has been illuminated by the recent discovery of supersulfides, a novel class of biomolecules, made possible through advancements in technology and analytical methods. These breakthroughs are reshaping our understanding of biological processes and emphasizing the intricate interplay between oxygen and sulfur in regulating essential redox reactions. This review summarizes the latest insights into the biological roles of sulfur and oxygen, their interdependence in key processes, and their contributions to adaptive responses to environmental stressors. By exploring these interactions, we aim to provide a comprehensive perspective on how these elements drive survival strategies across diverse life forms, highlighting their indispensable roles in both human health and the sustenance of life.

Ovarian cancer is characterized by a high rate of recurrence and a poor prognosis. Ferroptosis, a programmed cell death that is dependent on iron and lipid peroxidation, has emerged as a novel therapeutic target in recent years. This study investigated the effects of Obacunone, a naturally occurring compound present in citrus fruits, on the induction of ferroptosis in ovarian cancer via the Akt/p53 signaling pathway. SKOV3 and OVCAR3 ovarian cancer cell lines were utilized in vitro, while a BALB/c nude mouse model was employed for in vivo experiments. Cell proliferation was assessed utilizing the CCK-8 assay and EDU incorporation. The western blot technique was employed to assess the expression levels of proteins associated with the Akt/p53 signaling pathway. The ferroptosis inhibitor Fer-1 and the Akt activator SC79 were utilized to investigate the potential mechanism of action of Obacunone. Obacunone significantly inhibited the proliferation of ovarian cancer cells and induced ferroptosis, as evidenced by increased intracellular iron content, elevated lipid peroxidation levels, and abnormal mitochondrial morphology. Obacunone also decreased GSH levels, inhibited GPX4 expression and up-regulated ACSL4, as well as reduced Akt phosphorylation and enhanced p53 expression. In vivo experiments showed that Obacunone effectively inhibited tumor growth. Obacunone exhibits potential therapeutic significance through the modulation of the Akt/p53 signaling pathway, which may induce ferroptosis and inhibit the proliferation of ovarian cancer cells.

Ferroptosis is a regulated form of cell death characterised by iron-dependent lipid peroxidation, a process intricately linked to cellular redox homeostasis. This form of cell death is induced by the accumulation of intracellular iron and the subsequent generation of reactive oxygen species (ROS), which leads to lipid peroxidation and ultimately cell death. Ferroptosis is distinct from traditional forms of cell death, such as apoptosis, and holds significant therapeutic potential, particularly in cancers harboring rat sarcoma virus (RAS) mutations, such as epithelial ovarian cancer (EOC). EOC is notoriously resistant to conventional therapies and is associated with a poor prognosis. In this review, we examine recent progress in the understanding of ferroptosis, with a particular focus on its redox biology and the complex regulatory networks involved. We also propose a novel classification system for ferroptosis modulators, grouping them into six categories (I, II, III, IV, V and VI) based on their mechanisms of action and their roles in modulating cellular redox status. By refining these categories, we aim to provide deeper insights into the role of ferroptosis in cancer biology, especially in EOC, and to identify potential therapeutic avenues. We propose that further investigation of ferroptosis in the context of redox biology could reveal novel biomarkers and therapeutic targets, offering promising strategies to overcome resistance mechanisms and improve clinical outcomes for patients with EOC and other treatment-resistant cancers.

Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme in de novo lipogenesis. Here, we show a unique function of ACC in disrupting cellular iron homeostasis to drive ferroptosis, an iron-dependent, lipid peroxidation-induced form of cell death. We observed neuronal lipid accumulation and elevated labile iron pool associated with ACC dephosphorylation in mouse models of obstructive sleep apnea (OSA), a highly prevalent neurodegenerative disorder. ACC gene (Acaca) knockout (KO) or inhibition of its enzymatic activity rescued cellular iron metabolism through restoring lysosomal integrity and function, suppressing neuronal ferroptosis. ACC inactivation-driven lysosomal iron homeostasis requires the NFE2L2/NRF2-TFEB axis. Empagliflozin mitigates cellular iron overload via the ACC-NRF2-TFEB-lysosome pathway to alleviate neuronal ferroptosis, cognitive impairment, and mood dysfunction in OSA mice. Furthermore, inhibiting neuronal ACC reduces microglial activation, characterized by elevated complement proteins and pro-inflammatory cytokines, while microglia-specific C1qa KO prevents neuronal injury in OSA mice. Our findings identify a unique coupling between iron homeostasis and lipogenic signaling, suggesting ACC as a potential therapeutic target for neuronal ferroptosis and the resultant microgliosis in neurodegenerative diseases.

Cardiovascular diseases (CVDs) are characterized by high morbidity and mortality rates, imposing substantial epidemiological and economic burdens worldwide. Among the multifaceted mechanisms implicated in CVDs, autophagy and ferroptosis, two intimately linked cellular processes, emerge as pivotal pathophysiological contributors. Autophagy, as an evolutionary conserved process that mediates the degradation and recycling of intracellular components, including proteins and organelles, exerts critical regulatory effects on iron metabolism and lipid homeostasis through various specialized forms, including ferritinophagy and lipophagy. Conversely, ferroptosis, an iron dependent form of cell death, involves oxidative stress and the accumulation of lipid peroxides, often triggered by iron overload and the dysfunction of glutathione peroxidase 4 (GPX4). The intricate crosstalk between these two processes, particularly ferritinophagy-mediated iron regulation influencing ferroptosis, plays a crucial role in diverse CVDs contexts. Key regulatory molecules, such as Beclin-1 and nuclear factor E2-related factor 2 (Nrf2), function as central hubs, orchestrating the intricate interplay between autophagy and ferroptosis. Through a comprehensive examination of these mechanisms across various CVDs pathologies, we summarize the latest findings and outline potential therapeutic strategies targeting the crosstalk between autophagy and ferroptosis. As the inaugural review focusing on autophagy-ferroptosis interactions in CVDs, this work significantly enriches our understanding of the pathophysiology of CVDs and identifies novel therapeutic targets with potential for precision medicine interventions in managing CVDs.

The purpose of this study was to study the mechanism of the increased sensitivity of breast cancer tamoxifen-resistant strains by enhancing ferroptosis. CCK-8 and colony formation were used to detect cell proliferation. Ferroptosis indicator reactive oxygen species (ROS), glutathione (GSH) activity, ATP activity, Fe2+ content, and GPX4 protein expression were detected using ROS assay kit, reduced GSH content assay kit, ATP content assay kit, ferrous ion content assay kit, and western blotting, respectively. The protein levels of HO-1 and Nrf2-central regulators of antioxidant defense and ferroptosis resistance-were assessed by western blot. Tumor changes were observed in nude mice with subcutaneous tumorigenesis. Tamoxifen treatment reduced cell proliferation and colony formation, decreased GSH levels, and downregulated the expression of GPX4, Nrf2, and HO-1. Conversely, it increased ROS fluorescence intensity and Fe2⁺ accumulation and impaired the formation of MCF-7 organoids. Overexpression of Nrf2 reversed the effect of tamoxifen. Compared with MCF-7 treated with tamoxifen, in MCF-7 TAMR treated with tamoxifen, the cell proliferation, clone number, ATP activity, and the mRNA expression of Nrf2 and HO-1 significantly increased. The subcutaneous tumor formation experiment in nude mice confirmed that tumors simultaneously treated with ML385 and tamoxifen can further shrink the tumor. The expression of Nrf2 in clinical breast cancer and recurrent breast cancer tissues was significantly higher than that in paracancerous and primary breast cancer tissues, respectively. ML385, the inhibitor of Nrf2, increased ferroptosis via inhibiting Nrf2/HO-1 pathway to enhance the sensitivity of MCF-7 TAMR to tamoxifen.

Hypericin (HYP), a primary active compound derived from hypericum perforatum has been studied in the context of diabetes. The purpose of this study is to observe whether HYP can improve diabetic cardiac autonomic neuropathy (DCAN) and its possible mechanism. The current findings suggest that multiple drivers of ferroptosis in DCAN converge on the antioxidant protein nuclear factor erythroid 2-related factor 2(Nrf2). Overactivated P2X7 receptor (P2X7R) increases Nrf2 degradation by increasing proteasome activity through calcium ion accumulation. This work showed that HYP inhibited P2X7R expression, leading to elevated Nrf2 levels, thereby counteracting ferroptosis. This inhibition improves abnormal changes in cardiac function during the pathological process of DCAN in diabetic rats, including heart rate (HR), blood pressure (BP), heart rate variability (HRV), and sympathetic nerve discharge (SND). In summary, HYP enhances Nrf2 protein levels by suppressing P2X7R expression, reducing calcium-induced proteasome activity, and inhibits ferroptosis and inflammation. Thus, HYP alleviated DCAN progression.

While the tumor-suppressive functions of p53 are well established, the role of its homolog, TAp73, in cancer remains incompletely characterized and is a subject of active investigation. In this study, we observed downregulation of TAp73 protein expression in cervical cancer tissues, which significantly correlated with adverse clinical outcomes. Through co-expression network analysis, we identified functional associations between TAp73 and key pathways involved in lipid metabolism and redox homeostasis-both critical regulators of ferroptosis, an iron-dependent form of programmed cell death mediated by lipid peroxidation. Mechanistically, we demonstrate that TAp73 promotes ferroptosis by directly upregulating the transcription of β-transducin repeat-containing protein (β-TRCP), thereby facilitating the ubiquitin-dependent degradation of nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of cellular antioxidant defenses. This TAp73-mediated suppression of NRF2 activity renders cells more susceptible to ferroptotic death. Furthermore, TAp73 expression is transcriptionally induced during ferroptosis through the combined inactivation of enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive complex 2, and activation of E2F transcription factor 1 (E2F1). Notably, pharmacological inhibition of EZH2 synergized with sulfasalazine (SAS) to enhance ferroptosis in vivo, an effect largely dependent on TAp73. Together, these findings delineate a novel ferroptosis regulatory axis-EZH2/TAp73/β-TRCP/NRF2-and highlight its potential as a therapeutic target for cervical cancer intervention.

Age-related macular degeneration (AMD) is the leading cause of vision loss in the Western world, and it currently lacks effective therapy. It is believed that AMD initiates in the aged retinal pigment epithelium (RPE), which presents lysosomal dysfunction and oxidative stress (OxS) that ultimately leads to RPE damage and AMD progression. AMD is a complex pathology, so multitarget treatments are required to act on different pathways, presenting several challenges. In this review, we discuss the current knowledge on the pathogenesis of this disease, focusing mainly on lysosomal dysfunction and OxS. Because transcription factors regulate homeostasis, the transcription factor EB (TFEB), which controls lysosomal function and biogenesis, and the nuclear factor erythroid 2-related factor 2 (NRF2), which manages OxS, have been proposed as promising targets for disease intervention. Finally, we discuss the interplay of these pathways for a potential synergistic effect on AMD-targeted therapies, as they could change the course of today's available treatments for AMD.

Acute pancreatitis (AP) is characterised by inflammation and cell death in pancreatic tissue, with ferroptosis playing a critical role in its pathophysiology by mediating cellular damage and exacerbating inflammation. This study investigated the role of human leukocyte antigen (HLA)-F adjacent transcript 10 (FAT10) in AP, specifically its involvement in ferroptosis within pancreatic acinar cells. We observed that FAT10 expression was significantly elevated in AP tissues, which correlated with increased ferroptosis. Overexpression of FAT10 in pancreatic acinar cells enhances ferroptosis, whereas its knockdown reduced levels of ferroptosis markers. Furthermore, we confirmed that FAT10 enhanced ferroptosis in pancreatic acinar cells primarily by upregulating nuclear receptor coactivator 4 (NCOA4) expression. Mechanistic investigations revealed that FAT10 regulates NCOA4 expression to promote ferroptosis in a complex manner. FAT10 inhibits NCOA4 ubiquitination by reducing ubiquitin-NCOA4 complexes. Meanwhile, NCOA4 expression increased alongside the increase in FAT10-NCOA4 complexes, which are resistant to proteasomal degradation. Notably, we identified silibinin, a natural compound, as an effective inhibitor of the FAT10-NCOA4 axis, leading to reduced ferroptosis and alleviation of pancreatic damage in vivo. Silibinin treatment decreased the levels of ferroptosis-related proteins and inflammatory markers in both cell and animal models. Our findings highlight the FAT10-NCOA4 axis as a crucial regulator of ferroptosis in pancreatic acinar cells and suggest that targeting this pathway could offer a therapeutic strategy for mitigating AP. This study provides new insights into the regulatory mechanisms of ferroptosis in pancreatic acinar cells, identifying FAT10 as a potential therapeutic target for AP management.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a central role in regulating cellular responses to oxidative stress. It governs the expression of a broad range of genes involved in antioxidant defense, detoxification, metabolism, and other cytoprotective pathways. In normal cells, the transient activation of Nrf2 serves as a protective mechanism to maintain redox homeostasis. However, the persistent or aberrant activation of Nrf2 in cancer cells has been implicated in tumor progression, metabolic reprogramming, and resistance to chemotherapy and radiotherapy. These dual roles underscore the complexity of Nrf2 signaling and its potential as a therapeutic target. A deeper understanding of Nrf2 regulation in both normal and malignant contexts is essential for the development of effective Nrf2-targeted therapies. This review provides a comprehensive overview of Nrf2 regulation and function, highlighting its unique features in cancer biology, particularly its role in metabolic adaptation and drug resistance. Special attention is given to the current knowledge of Nrf2's involvement in leukemia and emerging strategies for its therapeutic modulation.

Oxytosis/ferroptosis is a form of non-apoptotic regulated cell death characterized by specific changes in the redox balance that lead to lethal lipid peroxidation. It has been hypothesized recently that aging predisposes the brain to the activation of oxytosis/ferroptosis in Alzheimer's disease (AD), and consequently that inhibition of oxytosis/ferroptosis offers a path to develop a new class of therapeutics for the disease. The goal of the present study was to investigate the occurrence of oxytosis/ferroptosis in the AD brain by examining transcriptomic signatures of oxytosis/ferroptosis in cellular and animal models of AD as well as in human AD brain samples.

Since oxytosis/ferroptosis has been poorly defined at the RNA level, the publicly available datasets are limited. To address this limitation, we developed TrioSig, a gene signature generated from transcriptomic data of human microglia, astrocytes, and neurons treated with inducers of oxytosis/ferroptosis. It is shown that the different signatures of oxytosis/ferroptosis are enriched to varying extents in the brains of AD mice and human AD patients. The TrioSig signature was the most frequently found enriched, and bioinformatic analysis of its composition identified genes involved in the integrated stress response (ISR). It was confirmed in nerve cell culture that oxytosis/ferroptosis induces the ISR via phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and activating transcription factor 4 (ATF4) signaling.

Our data support the involvement of oxytosis/ferroptosis in AD. The implications of the ISR for the progression and prevention of AD are discussed.

To observe the effect of electro-acupuncture (EA) on cardiomyocytes ferroptosis induced by myocardial ischemia/reperfusion injury (MIRI) in mice and to investigate whether this effect occurs via the nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signalling pathway.

Firstly, Fe2+ in the hearts and serum of mice from both the sham-operated (SO) group and MIRI group was measured to ascertain whether ferroptosis had occurred in the cardiomyocytes of mice in MIRI group. In the second phase, EA was administered, with sham acupuncture (SA) group as the comparator, to investigate the protective effects of EA on ferroptosis in MIRI cardiomyocytes and cardiac function. Additionally, we studied the levels of Nrf2 and HO-1 within the myocardium. In the third phase, Nrf2 inhibitor ML385 and agonist DMF were applied to observe the impact of inhibiting Nrf2 on the therapeutic efficacy of EA.

Compared with SO group, MIRI group showed increased iron deposition, along with a significant decrease in Nrf2 and HO-1 levels. Compared with MIRI group, MIRI + EA group exhibited significantly improved cardiac function and reduced cardiac iron deposition, accompanied by increased Nrf2 and HO-1 levels. Furthermore, the therapeutic effect of MIRI + EA group was superior to that of MIRI + SA group. Administration of ML385 partially blocked the anti-ferroptotic and cardioprotective effects of EA, while EA treatment exhibited similar effects to dimethyl fumarate (DMF) intervention.

EA alleviates ferroptosis-induced damage in MIRI in mice via the Nrf2/HO-1 pathway, providing modern scientific evidence for the application of acupuncture in the treatment of cardiovascular diseases.

SCARA5 (Scavenger Receptor Class A Member 5), a member of scavenger receptor class A, is a type II transmembrane protein. Previous studies, including our own, have suggested that SCARA5 acts as a tumor suppressor in various cancers. Additionally, SCARA5 has been identified as a ferritin receptor that facilitates iron delivery independent of transferrin. However, it remains unclear whether ferroptosis is involved in the tumor-suppressive function of SCARA5 in hepatocellular carcinoma (HCC). In this study, we found that SCARA5-deficient cells, including mouse embryonic fibroblasts (MEFs) and HCC cells, exhibited reduced sensitivity to ferroptosis induced by erastin and RSL3. We measured the cell viability, cellular reactive oxygen species (ROS), lipid ROS, malondialdehyde (MDA) and ferrous iron concentration to assess the role of SCARA5 in ferroptosis. Mechanistically, we confirmed that SCARA5 might enhance the intracellular availability of bioactive ferrous iron by promoting autophagic degradation of the major iron storage protein ferritin. Furthermore, we found that SCARA5 deficiency contributed to the resistance of HCC cells to sorafenib, a therapeutic agent for HCC, possibly by inhibiting ferroptosis. Collectively, our study revealed the role of SCARA5 in regulating ferroptosis, providing a profound understanding of sorafenib resistance in HCC systemic therapy.

Iron toxicity intricately links with ferroptosis, a unique form of cell death, and is significantly influenced by lipid peroxidation. Despite its critical role in various diseases and drug development, the association between iron toxicity and ferroptosis remains relatively unexplored. Accidental iron ingestion has emerged as a growing concern, resulting in a spectrum of symptoms ranging from gastrointestinal discomfort to severe outcomes, including mortality. This research introduces tannic acid (TA), which contains numerous phenol groups, as a powerful antiferroptotic agent. In male Wistar rats, even a modest dose of TA (7.5 mg/kg) significantly curtailed thiobarbituric acid reactive substances (TBARS), a well-established indicator of lipid peroxidation, and mitigated iron accumulation induced by ferrous sulfate (FeSO4) in the liver and kidney. The evidence supporting TA's protective function against iron-triggered liver and kidney dysfunction was substantiated by assessing specifically the levels of blood urea nitrogen (BUN) and alanine aminotransferase (ALT). In cell models using ferroptosis inducers such as iron-salophene (FeSP) and RAS-selective lethal 3 (RSL3), tannic acid (TA) exhibited superior protective capabilities compared to the traditional iron chelator, deferoxamine (DFO). Nrf2 and HO-1, regulators of antioxidant defense genes, are implicated in controlling ferroptosis. The expression of Nrf2 and HO-1 increased with TA treatment in the presence of FeSP, indicating their role in reducing lipid ROS levels. Additionally, TA significantly reduced the heightened levels of COX2, a marker associated with ferroptosis. In summary, the remarkable antiferroptosis activity of TA is likely due to its combined iron-chelating and antioxidant properties. With its safety profile for oral consumption, TA may offer benefits in cases of accidental iron ingestion and conditions like hemochromatosis.

Sepsis-induced acute lung injury (ALI) is driven by inflammation, oxidative stress, and immune suppression. MAPK14 (p38α) plays a role in ferroptosis and immune regulation, but its specific function in pediatric sepsis remains unclear. Therefore, our study aimed to explore the role and underlying mechanism of MAPK14 in pediatric sepsis.

Bioinformatics analysis of GSE26440 and FerrDb identified ferroptosis-related genes in pediatric sepsis. STRING database was used to predict the proteins associated with MAPK14. MAPK14 expression in whole blood samples, LPS-treated MLE-12 cells, and a CLP mouse model was detected by qRT-PCR and western blot. Ferroptosis was assessed by measuring MDA, GSH, and Fe2+ levels, while ROS accumulation was analyzed using DCFH-DA staining and DHE staining. A cycloheximide (CHX) assay was performed to assess TTP53 protein stability. MPO immunohistochemistry and PD-L1 immunofluorescence assessed neutrophil infiltration, and flow cytometry evaluated neutrophil apoptosis.

Bioinformatics analysis of GSE26440 and FerrDb identified MAPK14 as a ferroptosis-related gene in pediatric sepsis. MAPK14 expression was upregulated in sepsis patient samples, LPS-treated MLE-12 cells and CLP mouse lung tissues. Overexpression of MAPK14 led to increased MDA and Fe2+ levels, reduced GSH, and elevated ROS fluorescence intensity, confirming its role in promoting ferroptosis. Mechanistically, MAPK14 upregulated TTP53, which in turn suppressed SLC7A11 and GPX4, further driving ferroptosis. MAPK14 overexpression stabilized TTP53 and enhanced its activity. Additionally, MAPK14 enhanced MPO and PD-L1 expression to promote neutrophil infiltration and immune suppression. Additionally, MAPK14 overexpression inhibited neutrophil apoptosis, promoted neutrophil infiltration and enhanced immune suppression.

MAPK14 drives ferroptosis via the TTP53/SLC7A11/GPX4 pathway and exacerbates immune suppression by promoting neutrophil infiltration.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide, with macrophage dysfunction playing a central role in its pathogenesis. Ubiquitination, a critical post-translational modification, regulates diverse macrophage functions, including lipoprotein metabolism, inflammation, oxidative stress, mitophagy, autophagy, efferocytosis, and programmed cell death (pyroptosis, necroptosis, ferroptosis, and apoptosis). This review highlights the regulatory roles of ubiquitination in macrophage-driven CVD progression, focusing on its effects on cholesterol metabolism, inflammation, activation, polarization, and the survival of macrophages. Targeting ubiquitination pathways has therapeutic potential by enhancing macrophage autophagy, reducing inflammation, and improving plaque stability. However, challenges, such as off-target effects, ubiquitination crosstalk, and macrophage heterogeneity, must be addressed. By integrating advances in ubiquitination biology, therapeutic strategies can be developed to mitigate CVD and other macrophage-driven inflammatory diseases. This review underscores the potential of ubiquitination-targeting therapies for mitigating CVD and highlights the key areas for further investigation.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by recurrent injury to alveolar epithelial cells, epithelial-mesenchymal transition, and fibroblast activation, which leads to excessive deposition of extracellular matrix (ECM) proteins. However, effective preventative and therapeutic interventions are currently lacking. Ferroptosis, a unique form of iron-dependent lipid peroxidation-induced cell death, exhibits distinct morphological, physiological, and biochemical features compared to traditional programmed cell death. Recent studies have revealed a close relationship between iron homeostasis and the pathogenesis of pulmonary interstitial fibrosis. Ferroptosis exacerbates tissue damage and plays a crucial role in regulating tissue repair and the pathological processes involved. It leads to recurrent epithelial injury, where dysregulated epithelial cells undergo epithelial-mesenchymal transition via multiple signaling pathways, resulting in the excessive release of cytokines and growth factors. This dysregulated environment promotes the activation of pulmonary fibroblasts, ultimately culminating in pulmonary fibrosis. This review summarizes the latest advancements in ferroptosis research and its role in the pathogenesis and treatment of IPF, highlighting the significant potential of targeting ferroptosis for IPF management. Importantly, despite the rapid developments in this emerging research field, ferroptosis studies continue to face several challenges and issues. This review also aims to propose solutions to these challenges and discusses key concepts and pressing questions for the future exploration of ferroptosis.

Balanced mTOR activity and iron levels are crucial for muscle integrity, with evidence suggesting mTOR regulates cellular iron homeostasis. In this study, we investigated iron metabolism in muscle-specific mTOR knockout mice (mTORmKO) and its relation to their myopathy. The mTORmKO mice exhibited distinct iron content patterns across muscle types and ages. Slow-twitch soleus muscles initially showed reduced iron levels in young mice, which increased with the dystrophy progression but remained within control ranges. In contrast, the less affected fast-twitch muscles maintained near-normal iron levels from a young age. Interestingly, both mTORmKO muscle types exhibited iron metabolism markers indicative of iron excess, including decreased transferrin receptor 1 (TFR1) and increased levels of ferritin (FTL) and ferroportin (FPN) proteins. Paradoxically, these changes were accompanied by downregulated Ftl and Fpn mRNA levels, indicating post-transcriptional regulation. This discordant regulation resulted from disruption of key iron metabolism pathways, including NRF2/NFE2L2, HIFs, and AKT/PKB signaling. Mechanistically, mTOR deficiency impaired transcriptional regulation of iron-related genes mediated by NRF2 and HIFs. Furthermore, it triggered ferritin accumulation through two NRF2 mechanisms: (1) derepression of ferritin translation via suppression of the FBXL5-IRP axis, and (2) autophagosomal sequestration driven by NCOA4-dependent ferritin targeting to autophagosomes, coupled with age-related impairments of autophagy linked to chronic AKT/PKB activation. Three-week spermidine supplementation in older mTORmKO mice was associated with normalized AKT/PKB-FOXO signaling, increased endolysosomal FTL and reduced total FTL levels in the dystrophic soleus muscle. These findings underscore mTOR's crucial role in skeletal muscle iron metabolism and suggest spermidine as a potential strategy to address impaired ferritinophagy due to autophagy blockade in dystrophic muscle.

Oxidation of lipids, excessive cell death, and iron deposition are prominent features of human atherosclerotic plaques. While extensive research has established the detrimental roles of lipid oxidation and apoptosis in atherosclerosis development, the involvement of iron in atherogenesis is not yet fully understood. With the emergence of an iron-dependent form of cell death termed ferroptosis, new attention has been brought to the complex inter-play among iron, ferroptosis, and atherosclerosis. Mechanistically, ferroptosis is caused by the lethal accumulation of iron-mediated lipid peroxides. Emerging studies have underscored ferroptosis as a contributor to worsened atherosclerosis. Herein, we review the evidence that oxidative damage and iron overload in the context of atherosclerosis may promote ferroptosis within plaques. Furthermore, we summarize recent findings of lipid peroxidation, thereby potentially ferroptosis, in various plaque cell types-such as endothelial cells, macrophages, dendritic cells, T cells, and vascular smooth muscle cells-across different stages of atherosclerosis. Understanding how these processes influence atherosclerotic plaque progression may permit targeting stage-dependent ferroptosis in each cell population and could provide a rationale for developing cell type-specific intervention strategies to mitigate atherogenic ferroptosis effectively.

Post-stroke depression (PSD) poses a serious impact on patients' life quality. Effective drugs to treat this annoying disease are still being sought. Yi-nao-jie-yu (YNJY) prescription has been found to relieve PSD; however, the underlying mechanisms remain unelucidated. This work elucidated the therapeutic effects and mechanisms underlying YNJY prescription in PSD. PSD rat model was treated with YNJY prescription and ML385. Depression-like behaviors of rats was appraised. Hematoxylin-eosin, Nissl, and NeuN immunofluorescence staining were performed to observe hippocampal neuronal damage. Transmission electron microscopy was used to assess hippocampal mitochondrial damage. Commercial kits and western blotting were adopted to research ferroptosis-related factors and Nrf2/GPX4/SLC7A11 signals. In vitro experiments were performed using rat hippocampal neurons to explore the mechanism by which YNJY prescription relieves PSD. In PSD rats, YNJY prescription relieved depression-like behaviors, attenuated hippocampal neuronal damage, mitigated hippocampal ferroptosis and mitochondrial damage, and activated hippocampal Nrf2/GPX4/SLC7A11 pathway. By in vitro experiments, erastin treatment exacerbated hippocampal neuronal damage, ferroptosis, mitochondrial damage, and lipid peroxidation; however, YNJY prescription abolished these erastin-induced effects. In the erastin-treated hippocampal neuronal model of PSD, ML385 treatment increased ferroptosis, hippocampal neuronal damage, and lipid peroxidation; however, YNJY prescription counteracted these ML385-induced effects. By in vivo study, ML385 reversed the relief of YNJY prescription on depressive-like behaviors of PSD rats, and the inhibition on ferroptosis in PSD rats' hippocampus. YNJY prescription relieves PSD by blocking ferroptosis via activating the Nrf2/GPX4/SLC7A11 pathway. It may be a promising agent for treating PSD clinically.

Male infertility is intricately linked to dysregulated cell death pathways, including ferroptosis, cuproptosis, pyroptosis, and autophagy. Ferroptosis, driven by iron-dependent lipid peroxidation through the Fenton reaction and inactivation of the GPX4/Nrf2/SLC7A11 axis, disrupts spermatogenesis under conditions of oxidative stress, environmental toxin exposure, or metabolic disorders. Similarly, cuproptosis-characterized by mitochondrial dysfunction and disulfide stress due to copper overload-exacerbates germ cell apoptosis via FDX1 activation and NADPH depletion. Pyroptosis, mediated by the NLRP3 inflammasome and gasdermin D, amplifies testicular inflammation and germ cell loss via IL-1β/IL-18 release, particularly in response to environmental insults. Autophagy maintains testicular homeostasis by clearing damaged organelles and proteins; however, its dysregulation impairs sperm maturation and compromises blood-testis barrier integrity. These pathways intersect through shared regulators; reactive oxygen species and mTOR modulate the autophagy-pyroptosis balance, while Nrf2 and FDX1 bridge ferroptosis-cuproptosis crosstalk. Therapeutic interventions targeting these mechanisms have shown promise in preclinical models. However, challenges persist, including the tissue-specific roles of gasdermin isoforms, off-target effects of pharmacological inhibitors, and transgenerational epigenetic impacts of environmental toxins. This review synthesizes current molecular insights into the cell death pathways implicated in male infertility, emphasizing their interplay and translational potential for restoring spermatogenic function.

The high mortality rate associated with epithelial ovarian cancer (EOC) is primarily due to recurrence and chemoresistance, underscoring the urgent need for innovative therapeutic approaches that leverage newly identified vulnerabilities in cancer cells. While conventional chemotherapies induce apoptosis by targeting DNA or mitotic machinery, ferroptosis represents a new distinct form of programmed cell death characterised by the accumulation of lipid peroxides.

The sensitivity of different EOC cell lines to ferroptosis inducers was evaluated using cell viability assays and lipid peroxidation measurements. Live-cell imaging with the pH-sensitive CD63-pHuji reporter was performed to track the extracellular export of acyl-CoA synthetase long-chain family member 4 (ACSL4) via exosomes. The upstream regulator of ACSL4 were identified through immunoprecipitation-mass spectrometry (IP-MS) and validated using protein binding assays. Finally, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models were utilised to evaluate the therapeutic potential overcoming ferroptosis resistance.

In this study, we found that interferon (IFN)-γ combined with arachidonic acid (AA), which are endogenous ferroptosis inducers, could initiate ferroptosis in most EOC cells. However, some EOC cells displayed significant resistance. Contrary to the typical increase in ACSL4 protein observed in ferroptosis-sensitive cells, resistant EOC cells exhibited surprisingly low levels of this pro-ferroptotic lipid metabolic protein. Intriguingly, this reduction is attributed to the exosomal expulsion of ACSL4 protein, revealing a distinct cellular mechanism to evade ferroptosis. We further identified VIPAS39 as a pivotal regulator in sorting ACSL4 into late endosomes, thereby facilitating their subsequent release as exosomes. Notably, targeting VIPAS39 not only overcomes the resistance to ferroptotic cell death but also markedly suppresses tumour growth.

Our findings uncover the crucial role of VIPAS39 in ferroptosis evasion by facilitating the exporting of ACSL4 protein via exosomes, highlighting VIPAS39 as a promising target for ferroptosis-based anti-cancer therapy.

Funded by Beijing Municipal Natural Science Foundation (Key program Z220011), National Natural Science Foundation of China (NSFC) (T2225006, T2488301, 82272948), Peking University Medicine Youth Science and Technology Innovation 'Sail Plan' Project Type B Medical Interdisciplinary Seed Fund (71006Y3171), GuangDong Basic and Applied Basic Research Foundation (2021A1515110820), and the special fund of the National Clinical Key Speciality Construction Program, P. R. China (2023).

Nuclear receptor coactive 4 (NCOA4) is a specific receptor for ferritinophagy, transporting ferritin to lysosomal degradation, releasing free iron, and excessive iron levels may lead to cellular redox imbalance, contributing to cell death, predominantly ferroptosis. NCOA4 is regulated by a variety of transcriptional, post-transcriptional, translational, and post-translational modifications. Targeted modulation of NCOA4-mediated ferritinophagy has been successfully used as a therapeutic strategy in several disease models. Recent evidences have elucidated that ferritinophagy and ferroptosis played a major role in heavy metals toxicity. In this review, we explored the regulatory mechanism of NCOA4 as the sole receptor for ferritinophagy from multiple perspectives based on previous studies. The significant role of ferritinophagy-mediated ferroptosis in heavy metals toxicity was discussed in detail, emphasizing the great potential of NCOA4 as a target for heavy metals toxicity.

The magnetic properties of substances directly determine their response to an externally applied magnetic field, which are closely associated with magnetoreception, magnetic resonance imaging (MRI), and magnetic bioeffects. However, people's understanding of the magnetic properties of living organisms remains limited. In this study, we utilized NRF2 (nuclear factor erythroid 2-related factor 2) deficient mice to investigate the contribution of redox (oxidation-reduction) homeostasis, in which the key process is the transfer of electron, a direct target of magnetic field and origin of paramagnetism. Our results show that the NRF2-/- mice exhibit significantly altered systemic redox state, accompanied by increased magnetic susceptibility, particularly in the liver and spleen. Further analyses reveal that the levels of paramagnetic reactive oxygen species (ROS) in these tissues are markedly elevated compared to wild-type mice. Moreover, the concentrations of Fe2+ and Fe3+ are significantly elevated in NRF2-/- mice, which are directly correlated with the increased magnetic susceptibility. The disrupted redox balance in NRF2-/- mice not only exacerbates oxidative stress and iron deposition, but also induces impairment to the liver and spleen. The findings highlight the combined effects of ROS and iron metabolism in driving magnetic susceptibility changes, providing valuable theoretical insights for further research into magnetic bioeffects and organ-specific sensitivity to magnetic fields.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.

Large-scale studies indicate a strong relationship between the gut microbiome, type 2 diabetes mellitus (T2DM), and atherosclerotic cardiovascular disease (ASCVD). Here, a higher abundance of the type III secretion system (T3SS) virulence factors of Enterobacteriaceae/Escherichia-Shigella in patients with T2DM-related-ASCVD, which correlates with their atherosclerotic stenosis is reported. Overexpression of T3SS via Citrobacter rodentium (CR) infection in Apoe-/- T2DM mice exacerbated atherosclerotic lesion formation and increased gut permeability. Non-targeted metabolomic and proteomic analysis of mouse serum showed that T3SS caused abnormal glycerophospholipid metabolism in mice. Proteomics, RNA sequencing, and functional analyses showed that T3SS induced ferroptosis in intestinal epithelial cells, partly due to increased expression of ferritin heavy chains (FTH1). This findings first demonstrated that T3SS increases ferroptosis in intestinal epithelial cells, via disrupting the intestinal barrier and upregulation of phosphatidylcholine, thereby exacerbating T2DM-related ASCVD.