To investigate the role of ALKBH3 in acute myeloid leukemia (AML), we constructed an animal model of xenotransplantation of AML. Our study demonstrated that ALKBH3-mediated m1A demethylation inhibits ferroptosis in KG-1 cells by increasing ATF4 expression, thus promoting the development of AML. These findings suggest that reducing ALKBH3 expression may be a potential strategy to mitigate AML progression.

Background: Acute myeloid leukemia (AML) is characterized by the unrestrained proliferation of myeloid cells. Studies have shown that ALKBH3 is upregulated in most tumors, but the role of ALKBH3 in AML remains unclear.Methods: In this study, we investigated the function of ALKBH3 in AML cells (KG-1) by immunofluorescence, ELISA, flow cytometry, HE staining, and Western blotting.Results: Our results revealed that ALKBH3 is upregulated in AML and that the downregulation of ALKBH3 inhibited KG-1 cell proliferation and promoted cell apoptosis; at the same time, ALKBH3 upregulated ATF4 expression through m1A demethylation, and the knockdown of ATF4 resulted in increased ferrous iron content; TFR1, ACSL4, and PTGS2 expression; and ROS and MDA levels, whereas SOD and GSH levels and the expression levels of ATF4, SLC7A11, GPX4, and FTH1 decreased in KG-1 cells, thereby promoting ferroptosis. Mechanistically, ALKBH3-mediated m1A demethylation suppressed ferroptosis in KG-1 cells by increasing ATF4 expression, thereby promoting the development of AML.Conclusions: Our study indicated that reducing the expression of ALKBH3 might be a potential target for improving AML symptoms.

Hepatocellular carcinoma (HCC) presents formidable therapeutic challenges due to its pronounced metabolic heterogeneity, particularly arising from spatially uneven glucose availability within the tumor microenvironment (TME). To address this, we developed a glutathione (GSH)-responsive, biomimetic hybrid nanoenzyme system (M@GOx/Fe-HMON) composed of hollow mesoporous organosilica nanoparticles co-loaded with glucose oxidase (GOx) and Fe2+/Fe3+ redox pairs, and cloaked in homologous tumor cell membranes for enhanced targeting. In glucose-rich regions, the nanoenzyme orchestrates a GOx-peroxidase (POD) cascade that produces reactive oxygen species (ROS) via the Fenton reaction, leading to ferroptosis through intensified oxidative stress and GSH depletion. Conversely, under glucose-deficient conditions, the nanoenzyme promotes disulfidptosis by aggravating glucose deprivation, depleting nicotinamide adenine dinucleotide phosphate (NADPH), and impairing cystine metabolism, ultimately resulting in actin cytoskeletal collapse. This dual-action platform dynamically adapts to the tumor's metabolic landscape, selectively inducing ferroptosis or disulfidptosis according to glucose levels, disrupting redox homeostasis and amplifying antitumor efficacy. Notably, this study is the first to integrate ferroptosis and disulfidptosis activation into a single, metabolism-sensitive nanoenzyme system, providing a novel paradigm for exploiting tumor metabolic heterogeneity. Furthermore, the combination of endogenous metabolic regulation with magnetic resonance imaging (MRI)-guided diagnosis introduces an innovative and noninvasive strategy for precision cancer theranostics.

Ferroptosis is a type of iron‑dependent cell death characterized by excessive lipid peroxidation and may serve as a potential therapeutic target in cancer treatment. While the mechanisms governing ferroptosis continue to be explored and elucidated, an increasing body of research highlights the significant impact of epigenetic modifications on the sensitivity of cancer cells to ferroptosis. Epigenetic processes, such as DNA methylation, histone modifications and non‑coding RNAs, have been identified as key regulators that modulate the expression of ferroptosis‑related genes. These alterations can either enhance or inhibit the sensitivity of gastrointestinal cancer (GIC) cells to ferroptosis, thereby affecting the fate of GICs. Drugs that target epigenetic markers for advanced‑stage cancer have shown promising results in enhancing ferroptosis and inhibiting tumor growth. This review explores the intricate relationship between epigenetic regulation and ferroptosis in GICs. Additionally, the potential of leveraging epigenetic modifications to trigger ferroptosis in GICs is investigated. This review highlights the importance of further research to elucidate the specific mechanisms underlying epigenetic control of ferroptosis and to advance the development of novel therapeutic approaches.

Metabolic dysfunction-associated steatohepatitis (MASH) is a human health-threatening hepatic disease with limited treatment strategies. As a clinical Traditional Chinese Medicine compound for MASH, Shugan Xiaozhi (SGXZ) decoction has a definite effect, but its mechanism in treating MASH is still not very clear.

Exploring the potential mechanism of SGXZ decoction in treating MASH through multiomics and animal experimental validation.

UPLC-ESI-MS method was used to identify the main components of SGXZ decoction. Periodic acid-schiff (PAS), picrosirius red (PSR), and oil red o staining were used to assess the effect of SGXZ decoction on MCD-induced MASH mouse model. The mechanism of SGXZ decoction on MASH was analyzed using multiomics techniques. TUNEL staining, western blot (WB), immunohistochemistry (IHC), kits, transmission electron microscopy (TEM), and immunofluorescence (IF) were used to validate the mechanism of SGXZ decoction on MASH. Finally, molecular docking and molecular dynamics simulation were used to verify the targeting between key components of SGXZ decoction and important targets for intervention.

Through UPLC-ESI-MS analysis, 30 main active ingredients were obtained from SGXZ decoction. SGXZ decoction improved MASH, as evidenced by the improvement in histopathology, hepatic function indexes, lipid and fibrosis indicators. Both proteomic and transcriptomic results suggested an important role for ferroptosis in SGXZ decoction intervention in MASH, ferroptosis-related pathways were the main significant pathways obtained from these analyses. In addition, SGXZ decoction treatment reduced cell death, inflammation, and oxidative stress levels and restored impaired mitochondrial morphology in MCD-induced MASH mice. Furthermore, Mechanism experiments proved that SGXZ decoction treatment improved iron metabolism and lipid peroxidation imbalance and activated the Xc- system in MASH mice.

SGXZ decoction does have a therapeutic effect on MASH, and its mechanism may be related to its regulation of p53/ SLC7A11/GPX4 pathway to reduce ferroptosis.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent and progressive liver disorder posing a global health challenge. Oroxylin A, a naturally occurring flavonoid, with a broad spectrum of pharmacological activities. This study aimed to explore the therapeutic potential of oroxylin A and unravel its molecular mechanisms in mitigating high-fat diet (HFD)-induced NAFLD in murine models. Wild-type (WT) and nuclear factor erythroid 2-related factor 2 knockout (Nrf2-/-) mice were administered a HFD to generate in vivo models, while free fatty acids-treated HepG2 cells served as the in vitro model. To investigate the effects of oroxylin A, serum and liver biochemical markers, hepatic histology, lipid metabolism, and oxidative stress were assessed in a NAFLD mouse model. The underlying mechanisms of oroxylin A were further explored through Western blotting, immunohistochemistry, and immunofluorescence analysis. Oroxylin A mitigated hepatic steatosis and injury by reducing liver index, AST, ALT, TG, and TC levels, improving histology, and restoring lipid metabolism. Glucose and insulin tolerance tests demonstrated improved glucose homeostasis and insulin sensitivity. Moreover, oroxylin A suppressed inflammation, apoptosis, and fibrosis, while enhancing antioxidant defenses, and improving mitochondrial function. Mechanistically, oroxylin A activated the Keap1/Nrf2/GPX4/SLC7A11 axis, upregulating Nrf2 and HO-1. These effects were abolished in Nrf2-/- mice. In vitro results were consistent, and molecular docking, dynamics simulations, and CETSA confirmed its direct Keap1 binding. Oroxylin A protects against NAFLD by modulating the Nrf2 pathway, reducing oxidative stress and ferroptosis, making it a promising candidate for clinical NAFLD therapy.

As an essential nutrient for cancer cell survival, glutamine plays both promoting and inhibitory roles in ferroptosis; however, the underlying mechanisms remain obscure. Emerging evidence suggests that long noncoding RNAs (lncRNAs) are crucial regulators of ferroptosis. Nevertheless, it remains unclear whether lncRNAs are involved in glutamine-regulated ferroptosis. In this study, we report that the lncRNA FERRIN is induced by the transcription factor ATF4 under glutamine starvation conditions. FERRIN functions as an inhibitor of ferroptosis by upregulating SLC7A11 expression. Mechanistically, FERRIN interacts with the RNA binding protein hnRNPK, facilitating its binding to SLC7A11 mRNA and leading to the stabilization of SLC7A11 mRNA. Consistent with its inhibitory role in ferroptosis, FERRIN promotes in vitro cancer cell proliferation and in vivo xenograft tumor growth through its modulation of SLC7A11. Collectively, these findings establish FERRIN as a critical negative regulator of ferroptosis and suggest that FERRIN may represent an important link between glutamine availability and ferroptosis.

Intestinal senescence, often characterized by increased oxidative stress, is linked to gastrointestinal disorders such as inflammatory bowel disease and colorectal cancer. While previous studies have suggested that diets rich in food additives, such as the emulsifier Polysorbate 80 (P80), may influence gut health, the impact of P80 exposure on intestinal senescence remains unclear. This study aimed to explore the effects of P80 on intestinal senescence in a senescence-accelerated mouse prone model. The results revealed that P80 exposure could damage the intestinal barrier, induce oxidative stress, and accelerate intestinal senescence. Mechanistically, P80 activated the peroxisome proliferator-activated receptor-α (PPARα) and fatty acid-binding protein 1 (FABP1) axis, increasing intestinal fatty acid absorption and triggering lipotoxicity, which promoted senescence. Additionally, P80 exacerbated D-galactose-induced epithelial cell senescence and lipid accumulation via the PPARα signalling pathway. Importantly, the PPARα antagonist GW6471 mitigated fatty acid uptake and reduced senescence in the intestine. In conclusion, the emulsifier P80 accelerated intestinal senescence by regulating the PPARα-FABP1 axis to induce intestinal fatty acid uptake and lipotoxicity, suggesting new insights into the adverse effects of food additives on gut health.

Non-small cell lung cancer (NSCLC) is a fatal malignancy all over the world. Emerging studies have shown that curcumin might repress NSCLC progression by regulating ferroptosis, but the underlying mechanism remains unclear. 16HBE, LK-2, and H1650 cell viability was detected using Cell Counting Kit-8 assay. LK-2 and H1650 cell proliferation, apoptosis, and angiopoiesis were measured using 5-ethynyl-2'-deoxyuridine, flow cytometry, and tube formation assay. Superoxide dismutase, Malondialdehyde, Glutathione, and lactate dehydrogenase levels in LK-2 and H1650 cells were examined using special assay kits. Fe+ level was assessed using an iron assay kit. Doublesex and Mab-3 related Transcription Factor 3 (DMRT3) and solute carrier family 7 member 11 (SLC7A11) protein levels were detected using western in NSCLC tissues, adjacent matched normal tissues, 16HBE cells, LK-2 cells, H1650 cells, and xenograft tumor tissues. Glutathione peroxidase 4, Acyl-CoA Synthetase Long Chain Family Member 4, and transferrin receptor 1 protein levels in LK-2 and H1650 cells were examined by western blot assay. DMRT3 and SLC7A11 levels were determined using real-time quantitative polymerase chain reaction. After JASPAR prediction, binding between DMRT3 and SLC7A11 promoter was verified using Chromatin immunoprecipitation and dual-luciferase reporter assays in LK-2 and H1650 cells. Role of curcumin on NSCLC tumor growth was assessed using the xenograft tumor model in vivo. Curcumin blocked NSCLC cell proliferation and angiopoiesis, and induced apoptosis and ferroptosis. DMRT3 or SLC7A11 upregulation partly abolished the suppressive role of curcumin on NSCLC development. In mechanism, DMRT3 was a transcription factor of SLC7A11 and increased the transcription of SLC7A11 via binding to its promoter region. Curcumin inhibited NSCLC growth in vivo by modulating DMRT3. Curcumin might constrain NSCLC cell malignant phenotypes partly through the DMRT3/SLC7A11 axis, providing a promising therapeutic strategy for NSCLC.

Ovarian cancer (OC) is among the most common malignancies in the female reproductive system, marked by high rates of recurrence and mortality. Conventional chemotherapy, however, faces limitations due to the development of drug resistance, which hinders its effectiveness. Ferroptosis, an atypical form of programmed cell death distinct from autophagy, apoptosis, and necrosis, the relationship with tumors has become a hot research area in cancer studies in recent years. Anticancer therapies that target ferroptosis show strong potential in improving prognosis and counteracting chemotherapy resistance. Natural compounds, as a valuable source of novel targeted anticancer agents, its significant role in inhibiting tumor cell proliferation and metastasis and improving therapeutic sensitivity has been demonstrated in numerous existing studies. This review summarizes a range of natural compounds that target ferroptosis in OC cells, discussing their active components, mechanisms of action, and therapeutic potential, thereby providing useful insights for future targeted therapy and research in OC.

Qingyihuaji Formula (QYHJ) has been used to treat human pancreatic cancer for many years and are fully documented in the Pharmacopoeia of the People's Republic of China (2020 Edition), however, its pharmacological mechanisms remain largely unknown.

Here, we aimed to provide evidences for uncovering the underlying molecular mechanisms of QYHJ for pancreatic cancer management.

Bioinformatic analysis, quantitative real-time PCR, western blotting, glucose consumption, immunofluorescence and glycolytic activity assay were performed to determine the underlying mechanisms. The effects of QYHJ treatment, overexpression or knockdown of LINC00346 and ATF4 on the cell proliferation, migration, cellular ROS, apoptosis and metabolism were investigated. A xenograft mouse model was further established to evaluate the mechanism in vivo.

We found that QYHJ inhibits LINC00346-OMA1-ATF4 signal transduction and aerobic glycolysis in pancreatic cancer cells. Overexpression of LINC00346 and ATF4 reversed the inhibition of glycolytic metabolism and growth-suppressive effects after QYHJ treatment in vitro and in vivo. Moreover, there was a significant negative correlation between expression levels of LINC00346-OMA1 with overall survival in patients with pancreatic cancer and a positive correlation between OMA1 and ATF4 levels in human tumors.

Our findings indicate QYHJ shows the ability to suppress pancreatic cancer growth and progression, which is in mediated through antagonization of LINC00346 and activation of OMA1-ATF4. Targeting LINC00346-OMA1-ATF4 signaling may be promising effective therapeutic strategies for pancreatic cancer intervention.

Disulfidptosis, a newly identified regulated cell death, is linked to tumor progression, particularly in cancers with elevated SLC7A11 expression. This study investigates SLC7A11 expression in liver hepatocellular carcinoma (LIHC) and evaluates the therapeutic potential of ICG@C3F8-KL nanobubbles (NBs) combined with sonodynamic therapy (SDT) for inducing disulfidptosis. Bioinformatics analysis of TCGA datasets revealed upregulation of SLC7A11 in LIHC tissues. The synthesized ICG@C3F8-KL NBs exhibited a mean diameter of 156.46 nm and stable properties, with high encapsulation efficiencies of 51.32 % ± 0.7 % for KL and 80.15 % ± 0.21 % for ICG. In vitro, ICG@C3F8-KL NBs, under ultrasound, generated reactive oxygen species (ROS), enhancing cytotoxicity in HepG2 cells with an IC50 lower than KL alone. These NBs also inhibited cell migration and colony formation, suggesting disulfidptosis induction via altered glucose uptake and NADP+/NADPH ratio, as well as F-actin contraction. In vivo, ICG@C3F8-KL NBs accumulated in tumor tissues and suppressed growth without significant toxicity. Unsupervised clustering of disulfidptosis-related genes in TCGA LIHC cohort identified subtypes with distinct prognoses, and a predictive model based on five key genes was developed. In conclusion, ICG@C3F8-KL NBs, combined with ultrasound, effectively induce disulfidptosis, offering a promising strategy for LIHC treatment, with the potential for personalized therapy informed by disulfide-associated gene signatures.

Globally, drug-induced hepatotoxicity or drug-induced liver injury (DILI) is a serious clinical concern. Knowing the processes and patterns of cell death is essential for finding new therapeutic targets since there are not many alternatives to therapy for severe liver lesions. Excessive lipid peroxidation is a hallmark of ferroptosis, an iron-reliant non-apoptotic cell death linked to various liver pathologies. When iron is pathogenic, concomitant inflammation may exacerbate iron-mediated liver injury, and the hepatocyte necrosis that results is a key element in the fibrogenic response. The idea that dysregulated metabolic pathways and compromised iron homeostasis contribute to the development of liver injury by ferroptosis is being supported by new data. Various ferroptosis-linked genes and pathways have been linked to liver injury, although the molecular processes behind ferroptosis's pathogenicity are not well known. Here, we delve into the features of ferroptosis, the processes governing ferroptosis, and our current knowledge of iron metabolism. We also provide an overview of ferroptosis's involvement in the pathophysiology of liver injury, particularly DILI. Lastly, the therapeutic possibilities of ferroptosis targeting for liver injury management have been provided. Natural products, nanoparticles (NPs), mesenchymal stem cell (MSC), and their exosomes have attracted increasing attention among such therapeutics.

Metabolic dysfunction-associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD), still lacks approved effective clinical drugs. Ferroptosis, a form of regulated cell death driven by excessive iron accumulation and uncontrollable lipid peroxidation, has been proven to be a trigger of inflammation and initiation of steatohepatitis. The pathogenic interplay is modulated by oxidative stress, while the Nrf2-mediated antioxidant response plays a regulatory role in ferroptosis. Phytochemical hinokitiol (Hino) has demonstrated positive efficacy in hepatocellular carcinoma (HCC) in the reported work, but it remains unknown whether its therapeutic effect attributes to delaying the progress of steatohepatitis to HCC.

This work aimed to systemically investigate the significance of ferroptosis in the pathogenesis of MASH and to demonstrate that Hino, a bioactive monoterpene compound, attenuates the primary pathological characteristics of MASH via promotion of Nrf2/GPX4 signaling.

In this work, a MASH model was established using the high-fat/high-cholesterol (HFHC) diet-fed in vivo and palmitic acid/oleic acid (PO)-stimulated hepatocytes in vitro. Biochemical indexes, pathological analysis, western blot, PCR assay, energy metabolic phenotype, molecular docking, and confirmatory assays were performed comprehensively to reveal the key link between the Nrf2/GPX4 axis and the treatment of MASH.

Under MASH conditions with increased oxidative stress, we show that Nrf2 was remarkable downregulated in HFHC diet-fed mice and PO-managed hepatocytes. Mechanistically, hepatic upregulation of Nrf2 through phytochemical Hino supplementation inhibited ferroptosis, enhanced lipid metabolism, and thereby alleviated hepatic steatosis, inflammation, and fibrosis. Conversely, silencing Nrf2 in hepatocytes further promoted the accumulation of key markers of ferroptosis and aggravated MASH phenotypes.

Increased ferroptosis promoted steatosis which further drove inflammation and hepatic fibrosis. Our results suggested the significance of Nrf2 in ameliorating MASH, which was regulated through Hino. Thus, targeted inhibition of ferroptosis through Hino administration is a feasible and effective approach for treating MASH.

Currently, cancer immunotherapy strategies are primarily formulated based on the patient's present condition, representing a "static" treatment approach. However, cancer progression is inherently "dynamic," as the immune environment is not fixed but undergoes continuous changes. This dynamism is characterized by the ongoing interactions between tumor cells and immune cells, which ultimately lead to alterations in the tumor immune microenvironment. This process can be effectively elucidated by the concept of cancer immunoediting, which divides tumor development into three phases: "elimination," "equilibrium," and "escape." Consequently, adjusting immunotherapy regimens based on these distinct phases may enhance patient survival and improve prognosis. Targeting ferroptosis is an emerging area in cancer immunotherapy, and our findings reveal that the antioxidant systems associated with ferroptosis possess dual roles, functioning differently across the three phases of cancer immunoediting. Therefore, this review delve into the dual role of the ferroptosis antioxidant system in tumor development and progression. It also propose immunotherapy strategies targeting ferroptosis at different stages, ultimately aiming to illuminate the significant implications of targeting ferroptosis at various phases for cancer immunotherapy.

Current evidence indicates that circRNAs are involved in the development of multiple malignancies including hepatocellular carcinoma (HCC). However, the specific functions of circRNAs in HCC metabolism and progression and their underlying regulatory mechanisms remain unclear. We have identified a novel circRNA circMFN2, by bioinformatics analysis of circRNA microarray data from the GEO database. The levels of circMFN2 were assessed in HCC cell lines and tissues, and its clinical relevance was assessed. The effect of circMFN2 on HCC cells was evaluated in vitro and in vivo. The effect of ELK1 on glutaminolysis and HCC progression was also explored. Patients with HCC and high circMFN2 expression exhibited worse survival outcomes. Functionally, downregulation of circMFN2 repressed the proliferation, invasion, and migration of HCC cells in vitro, whereas ectopic expression of circMFN2 had the opposite effects. The effects of tumor enhancement by circMFN2 on HCC were confirmed by in vivo experiments. Mechanistically, circMFN2 acted as a sponge for miR-361-3p, leading to the upregulation of its target ELK1, whereas ELK1 was enriched in the MFN2 promoter to enhance the transcription and expression of MFN2, indirectly leading to the upregulation of circMFN2. Additionally, we found that circMFN2 promotes glutaminolysis in HCC by increasing ELK1 phosphorylation. We concluded that circMFN2 facilitates HCC progression via a circMFN2/miR-361-3p/ELK1 feedback loop, which promotes glutaminolysis mediated by the upregulation of phosphorylated ELK1. Therefore, circMFN2 not only serves as a potential prognostic indicator, but it could also serve as a therapeutic target for HCC. Further studies are warranted.

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.

Ferroptosis is a nonapoptotic form of cell death discovered in 2012. Noninvasive treatments regulating ferroptosis are important for a wide range of diseases. Among the noninvasive treatments, sonodynamic therapy (SDT) has become promising due to its strong tissue penetration and few side effects. In recent years, targeted drug delivery platforms constructed on the basis of SDT have provided an efficient delivery mode for the regulation of ferroptosis. Based on the latest research reports, this Perspective introduces the basic mechanism of SDT and the influencing factors of therapeutic effects, elucidates the significance of ferroptosis-targeted SDT, and summarizes the recent studies on ferroptosis-targeted SDT through different pathways. We also present innovative studies of composite ultrasound-responsive drug delivery platforms. Finally, a brief summary and outlook based on current ferroptosis-targeted SDT are presented.

Ferroptosis is an iron-dependent programmed death caused by the imbalance of lipid peroxides in cells. Unlike apoptosis, autophagy and necrosis, ferroptosis is mainly induced by the small molecule compound erastin. The main characteristics of ferroptosis were glutathione (GSH) depletion, inactivation of glutathione peroxidase 4 (GPX4) and reactive oxygen species (ROS) promoting lipid peroxidation. Eventually, the imbalance of lipid peroxidation regulation in cells leads to ferroptosis. The lipid metabolic pathway ultimately contributes to ferroptosis through the production of lipid peroxides. In addition, other cellular metabolic pathways can also regulate ferroptosis, such as the antioxidant metabolic pathway, which inhibits ferroptosis by clearing lipid peroxides and reducing cell membrane damage. Long non-coding RNAs (lncRNAs) are non-coding transcripts more than 200 nucleotides in length and are a less classified group of RNA transcripts that are associated with tumorigenesis and metastasis and are more tissue or cell type specific than protein-coding genes. Studies on the molecular profile of lncRNAs in plasma samples from liver cancer patients show that differentially expressed lncRNAs are mainly concentrated in biological functions related to tumorigenesis, such as cell metastasis, immune response and metabolic regulation. With different biological functions in physiological and pathological environments, the specific expression patterns of lncRNAs coordinate cell state, development, differentiation, and disease.

Ferroptosis denotes a distinct form of controlled cell death marked by substantial iron buildup and significant lipid peroxidation, playing a crucial role in several disease processes linked to cell death. Given the liver's essential functions in iron and lipid metabolism and its vulnerability to oxidative damage, more research has investigated the correlation between ferroptosis and numerous hepatic diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). NAFLD has arisen as a worldwide public health concern due to elevated morbidity and high death rates. The pathogenesis of MASLD remains incompletely elucidated. Recent data suggests that ferroptosis is crucial in the pathophysiology of MASLD; nevertheless, the specific processes by which ferroptosis influences MASLD remain unclear. The present review summarizes the molecular processes of ferroptosis and its intricate regulatory networks, outlines the differing impacts of ferroptosis at different stages of MASLD, and examines possible approaches targeting ferroptosis for the therapy of MASLD, suggesting a novel approach for its management.

The sequence of events associated with cancer cachexia induction needs to be further characterized. Using the C26 mouse model, we found that prior to cachexia, cancer progression was associated with increased levels of IL-6 and growth differentiation factor 15 (GDF15), highly induced production of positive acute phase proteins (APPs) and reduced levels of most amino acids in the systemic circulation, while signal transducer and activator of transcription 3 (STAT3) signaling was induced (1) in the growing spleen, alongside activation of ribosomal protein S6 (rpS6) and alpha subunit of eukaryotic translation initiation factor-2 (eIF2α) signalings, and (2) in the liver, alongside increased positive-APP expression, decreased albumin expression, and upregulation of autophagy. At the onset of cachexia, rpS6 and eIF2α signalings were concomitantly activated in the liver, with increased expression of activating transcription factor 4 (ATF4) target genes involved in amino acid synthesis and transport, as well as autophagy. Data show that pre-cachectic (pre-Cx) alterations in protein/aa homeostasis are followed by activation of eIF2α signaling in the liver, an adaptive mechanism likely regulating protein/amino acid metabolism upon progression to cachexia.

Hepatocellular carcinoma (HCC) is among the most common causes of cancer-related deaths worldwide. Previous studies showed that N6-methyladenosine (m6A), the most abundant chemical modification in eukaryotic RNAs, is implicated in HCC progression. Using liver-specific conditional knockout mice, we found that the loss of METTL3, the core catalytic subunit of m6A methyltransferase, significantly promoted hepatic tumor initiation under various oncogenic challenges, contrary to the previously reported oncogenic role of METTL3 in liver cancer cell lines or xenograft models. Mechanistically, we hypothesized that METTL3 deficiency accelerated HCC initiation by inhibiting m6A deposition on MANF transcripts, impairing nuclear export and thus MANF protein levels, which led to insufficient endoplasmic reticulum (ER) stress response pathway activation. Our findings suggest a tumor-suppressive role for METTL3 in the early stages of HCC, emphasizing the importance of understanding the dynamic role of epigenetic regulation in tumorigenesis and targeted therapy.

The initiation of calcium oxalate (CaOx) kidney stone formation is highly likely to stem from injury to the renal tubular epithelial cells (RTECs) induced by stimulation from an aberrant urinary environment. CHAC1 plays a critical role in stress response mechanisms by regulating glutathione metabolism. Endoplasmic reticulum (ER) stress and ferroptosis are demonstrated to be involved in stone formation. This study attempted to elucidate the mechanism of ER stress-dependent ferroptosis and the role of CHAC1 in CaOx kidney stones. Here, regulating ER stress and CHAC1 expression are performed in in vivo and in vitro stone models. These findings indicated that 4-Phenylbutyric acid (4-PBA)treatment and CHAC1 deficiency alleviated the ferroptotic status, including restoring GSH content, suppressing Fe2+ and lipid peroxidation accumulation, as well as regulating ferroptosis-related proteins. Notably, 4-PBA treatment and CHAC1 deficiency both attenuated oxidative damage, improved renal function, importantly, decreased crystal deposition. Additionally, ChIP-seq and ChIP-qPCR analyses demonstrated that CHAC1 is the vital downstream target gene of ATF4. The results indicated that ATF4 depletion inhibited the upregulation of CHAC1 and pro-ferroptotic response induced by Ox stimulation. Overall, ATF4/CHAC1 axis mediating ER stress-dependent ferroptosis may be a promising research direction for identifying potential strategy to prevent and treat CaOx kidney stones.

Acetochlor, a commonly used herbicide, poses significant risks to ecosystem and organism health through contamination of the food chain. Despite its widespread use, there is a lack of comprehensive studies on its toxicological effects on avian species. This study investigates the impact of environmental acetochlor exposure on chicken liver health using metabolomics analysis and histopathological techniques. Microscopic examination revealed autophagy-like structures and endoplasmic reticulum (ER) expansion, with significant effects observed at higher exposure levels. Biochemical analysis and metabolomics also demonstrated acetochlor-induced ferroptosis, highlighting disruptions in liver function. Further, in vitro studies revealed that acetochlor stimulates autophagy, which regulates ferroptosis via ferritin degradation, mediated through the ER-CaMKII pathway. These findings emphasize the importance of understanding the molecular mechanisms involved in acetochlor toxicity, particularly the role of the Ca2+/CaMKII pathway, ER stress, and autophagy in ferroptosis. The study contributes to a deeper understanding of how environmental contaminants affect avian species, providing critical insights for better herbicide risk assessment, pollution control, and sustainable agricultural practices.

Although ferroptosis as an emerging way exhibits tremendous promising in the therapy of hepatocellular carcinoma (HCC), the novel therapeutic agents targeting ferroptosis are still scarce. In our previous study, we found that the natural products toosendanin (TSN) possessed significant anti-proliferative efficacy by regulating WW domain-containing oxidoreductase (WWOX) in HCC. However, there is very limited understanding about TSN-induced ferroptosis, and the role of WWOX in ferroptosis has not been studied. In present study, we investigated the effect and underlying molecular mechanisms of TSN in WWOX-mediated ferroptosis in HCC. We found that TSN induced ferroptosis in HCC cells and its effect was dependent on WWOX. RNA-seq and RT-qPCR assay identified that TSN significantly increased spermidine/spermine N1-acetyltransferase 1 (SAT1) expression while decreased solute carrier family 40 member 1 (SLC40A1) expression, which play vital roles in ferrous ion transport. Further dual-luciferase reporter assay and Co-IP assay revealed that TSN-induced WWOX activation controlled the transcriptional activity of p53 and NF-E2-related factor 2 (NRF2) by regulating their interaction. Meanwhile, IF assay and WB assay confirmed that TSN increased the nuclear distribution of p-WWOX and p-p53 dimers, but impeded the nuclear translocation of NRF2 by inducing its ubiquitination degradation, ultimately regulating the transcription of their downstream target genes. In addition, the results from cell viability assay and the tumor xenograft model verified that co-treatment of TSN, ML385 (NRF2 inhibitor), and MIRA-1 (p53 activator) could effectively inhibit HCC cells growth in the presence of Fer-1 (ferroptosis inhibitor) in vitro and in vivo. Overall, our study contributes to the necessary understanding of the molecular mechanisms of WWOX-mediated ferroptosis regulation, and identifies TSN as a potential therapeutic agent targeting ferroptosis for HCC.

Hepatocellular carcinoma (HCC) is a major type of liver cancer and an important cause of cancer death. It has been reported that the hepatocyte death plays an important role in HCC. Ferroptosis is an iron-dependent programmed cell death characterized by the accumulation of free iron and lipid peroxidation. A series of studies have shown that ferroptosis contributes to the occurrence and development of HCC. MicroRNAs (miRNAs) are non-coding RNAs with a length of approximately 222 nt. In recent years, miRNAs have been shown to participate in regulating ferroptosis to play a vital role in HCC, but the related mechanisms are not fully understood. This review summarized the current understanding of ferroptosis, as well as the biogenesis and function of miRNAs, and focused on the role of miRNAs regulation of ferroptosis in HCC, with the hope of providing new targets and ideas for the treatment of HCC.

Diabetic kidney disease (DKD) is a prevalent complication of diabetes mellitus (DM), and its incidence is increasing alongside the number of diabetes cases. Effective treatment and long-term management of DKD present significant challenges; thus, a deeper understanding of its pathogenesis is essential to address this issue. Chronic inflammation and abnormal cell death in the kidney closely associate with DKD development. Recently, there has been considerable attention focused on immune cell infiltration into renal tissues and its inflammatory response's role in disease progression. Concurrently, ferroptosis-a novel form of cell death-has emerged as a critical factor in DKD pathogenesis, leading to increased glomerular filtration permeability, proteinuria, tubular injury, interstitial fibrosis, and other pathological processes. The cardiorenal benefits of SGLT2 inhibitors (SGLT2-i) in DKD patients have been demonstrated through numerous large clinical trials. Moreover, further exploratory experiments indicate these drugs may ameliorate serum and urinary markers of inflammation, such as TNF-α, and inhibit ferroptosis in DKD models. Consequently, investigating the interplay between ferroptosis and innate immune and inflammatory responses in DKD is essential for guiding future drug development. This review presents an overview of ferroptosis within the context of DKD, beginning with its core mechanisms and delving into its potential roles in DKD progression. We will also analyze how aberrant innate immune cells, molecules, and signaling pathways contribute to disease progression. Finally, we discuss the interactions between ferroptosis and immune responses, as well as targeted therapeutic agents, based on current evidence. By analyzing the interplay between ferroptosis and innate immunity alongside its inflammatory responses in DKD, we aim to provide insights for clinical management and drug development in this area.

The battle against cancer has evolved over centuries, from the early stages of surgical resection to contemporary treatments including chemotherapy, radiation, targeted therapies, and immunotherapies. Despite significant advances in cancer treatment over recent decades, these therapies remain limited by various challenges. Immune checkpoint inhibitors (ICIs), a cornerstone of tumor immunotherapy, have emerged as one of the most promising advancements in cancer treatment. Although ICIs, such as CTLA-4 and PD-1/PD-L1 inhibitors, have demonstrated clinical efficacy, their therapeutic impact remains suboptimal due to patient-specific variability and tumor immune resistance. Cell death is a fundamental process for maintaining tissue homeostasis and function. Recent research highlights that the combination of induced regulatory cell death (RCD) and ICIs can substantially enhance anti-tumor responses across multiple cancer types. In cells exhibiting high levels of recombinant solute carrier family 7 member 11 (SLC7A11) protein, glucose deprivation triggers a programmed cell death (PCD) pathway characterized by disulfide bond formation and REDOX (reduction-oxidation) reactions, termed "disulfidptosis." Studies suggest that disulfidptosis plays a critical role in the therapeutic efficacy of SLC7A11high cancers. Therefore, to investigate the potential synergy between disulfidptosis and ICIs, this study will explore the mechanisms of both processes in tumor progression, with the goal of enhancing the anti-tumor immune response of ICIs by targeting the intracellular disulfidptosis pathway.

Co-stimulatory molecules are imperative for CD8+ T cells to eliminate target cell and maintain sustained cytotoxicity. Despite an advanced understanding of the co-stimulatory molecules deficiency that results in tumor escape, the tumor cell-intrinsic mechanisms that regulate co-stimulatory molecules remain enigmatic, and an in-depth dissection could facilitate the improvement of treatment options. To this end, in this study, we report that the deficiency of the critical costimulatory molecule CD58, mediated by the expression of ATF4 in tumor cells, impairs the formation of immunological synapses (IS) and leads to the deterioration of antitumor immune function of CD8+ T cells. Mechanistically, ATF4 transcriptionally upregulated dynamin 1 (DNM1) expression leading to DNM1-dependent endocytosis (DDE)-mediated degradation of CD58. Furthermore, administration of DDE inhibitor prochlorperazine or ATF4 knockdown effectively restored CD58 expression, boosting CD8+ T cell cytotoxicity and immunotherapy efficiency. Thus, our study reveals that ATF4 in tumor cells weakens CD58 expression to interfere with complete IS formation, and indicates potential approaches to improve the cytolytic function of CD8+ T cell in tumor immunotherapy.

Gliomas are aggressive brain tumors known for their poor prognosis and resistance to standard treatment options. Ferroptosis is an iron-dependent form of regulated cell death that has emerged as a promising target for cancer treatment. This study examined how the methyltransferase-like 3/YTH domain family protein 1 (METTL3/YTHDF1) axis influences ferroptosis and glioma progression by stabilizing mitochondrial carrier homolog 2 (MTCH2) messenger RNA (mRNA).

MTCH2 expression in glioma tissues and cell lines was evaluated through quantitative real-time polymerase chain reaction (PCR) and western blot analyses. To assess the effects of MTCH2 knockdown and overexpression on glioma cell functions, we performed a series of functional assays, including cell viability, colony formation, and measurements of lipid reactive oxygen species (lipid ROS) and malondialdehyde (MDA) levels. Additionally, we conducted RNA immunoprecipitation (RIP) and RNA stability assays to explore the underlying mechanisms governing the interaction between METTL3, YTHDF1, and the stability of MTCH2 mRNA.

MTCH2 was significantly upregulated in glioma tissues and cell lines. Silencing of MTCH2 resulted in decreased glioma cell proliferation and induced ferroptosis, as evidenced by increased lipid peroxidation and ROS accumulation. Conversely, overexpression of MTCH2 enhanced glioma cell survival and reduced ferroptosis. METTL3-mediated N6-methyladenosine (m6A) modification enhanced MTCH2 mRNA stability by enabling YTHDF1 to bind and protect the modified mRNA from degradation.

The METTL3/YTHDF1/MTCH2 axis plays a critical role in glioma progression by inhibiting ferroptosis and promoting tumor cell survival. Targeting this pathway may provide a new and effective treatment strategy for glioma patients.

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the involvement of ferroptosis in its pathological mechanism. In this study, the effects and mechanism of BRCA1-associated protein 1 (BAP1) on neuronal ferroptosis in PD were evaluated. Methods: A PD mouse model was constructed by injecting mice with MPTP. Nissl staining, immunohistochemistry, immunofluorescence, and Prussian blue staining evaluated histopathology and iron distribution. The PD cell model was constructed by subjecting SK-N-SH cells to MPP+. The m6A level of BAP1 was assessed by MeRIP. mRNA levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, and SLC7A11 were evaluated utilizing RT-qPCR. Protein levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, SLC7A11, and p53 were measured by Western blot. Cell viability was assessed using CCK-8 assay, and TUNEL was used for assessing apoptosis. The levels of MDA, GSH, SOD, and Fe2+ were also measured. The interactions among molecules were verified using RIP assay, dual luciferase reporter assay, and ChIP assay. Results: SK-N-SH cells treated with MPP+ showed a decrease in overall m6A levels of BAP1. FTO facilitated m6A demethylation of BAP1, leading to an increased level of expression of BAP1. m6A-binding protein, YTHDF2 recognized and decayed methylated mRNA of BAP1, leading to the reduced BAP1 stability. The FTO/BAP1 axis promoted MPP+-induced ferroptosis by suppressing SLC7A11. BAP1, in collaboration with p53, reduced the level of expression of SLC7A11. Knocking down BAP1 mitigated ferroptosis in an MPTP mouse model. Conclusion: m6A-mediated modification of BAP1 regulates neuronal ferroptosis by cooperating with p53 to decrease the level of SLC7A11. Thus, BAP1 may be a potential therapeutic target for PD treatment.

SLC7A11, often called xCT, belongs to the SLC family of transporters, which mediates the cellular influx of cystine and the efflux of glutamate. These transport processes are crucial for synthesizing GSH, enhancing the cell's ability to mitigate oxidative stress (OS). Emerging studies highlight the pivotal role of OS in triggering and exacerbating various metabolic and endocrine disorders, underlining the critical importance of regulating SLC7A11 expression levels. This study reviews the diverse roles of SLC7A11 in endocrine and metabolic diseases, examining its relationship with the metabolism of three key nutrients: proteins and amino acids, carbohydrates, and lipids. Additionally, the involvement of SLC7A11 in the onset and development of various common endocrine and metabolic disorders is analyzed. Additionally, it provides an overview of the current clinical and experimental use of SLC7A11 inhibitors and agonists. This review aims to offer insightful perspectives into the involvement of SLC7A11 in endocrine and metabolic pathologies and to foster the development of innovative therapeutic strategies that target SLC7A11.

Within the tumor microenvironment, survival pressures are prevalent with potent drivers of tumor progression, angiogenesis, and therapeutic resistance. N6-methyladenosine (m6A) methylation has been recognized as a critical post-transcriptional mechanism regulating various aspects of mRNA metabolism. Understanding the intricate interplay between survival pressures and m6A modification provides new insights into the molecular mechanisms underlying hepatocellular carcinoma (HCC) progression and highlights the potential for targeting the survival pressures-m6A axis in HCC diagnosis and treatment.

A literature search was conducted in PubMed, MEDLINE, and Web of Science for relevant articles published up to April 2024. The keywords used for the search included hepatocellular carcinoma, cellular survival, survival pressure, N6-methyladenosine, tumor microenvironment, stress response, and hypoxia.

This review delves into the multifaceted roles of survival pressures and m6A RNA methylation in HCC, highlighting how survival pressures modulate the m6A landscape, the impact of m6A modification on survival pressure-responsive gene expression, and the consequent effects on HCC cell survival, proliferation, metastasis, and resistance to treatment. Furthermore, we explored the therapeutic potential of targeting this crosstalk, proposing strategies that leverage the understanding of survival pressures and m6A RNA methylation mechanisms to develop novel, and more effective treatments for HCC.

The interplay between survival pressures and m6A RNA methylation emerges as a complex regulatory network that influences HCC pathogenesis and progression.

Ischemia-free liver transplantation (IFLT) is developed as a novel clinical approach to avoid ischemia-reperfusion injury (IRI). This study aims to identify the most distinguished programmed cell death pathway in grafts undergoing IFLT versus conventional liver transplantation (CLT) and to explore the underlying mechanism. Ferroptosis is the most distinct programmed cell death form between IFLT and CLT grafts. Among various cell death inhibitors, the ferroptosis inhibitor (Ferrostain-1) is the most effective one to prevent hepatocytes from damage induced by oxygen deprivation/reoxygenation (OGD/R). Hepatocyte ferroptosis is significantly alleviated in IFLT versus CLT grafts in both human beings and pigs. Ubiquitination enzyme screening identifies augmented amounts of ubiquitin-specific protease 19 (USP19) in IFLT versus CLT grafts. The upregulation of USP19 in the grafts is correlated with reduced pathological Suzuki's score, lower post-transplant peak liver enzyme level, and less early allograft dysfunction in liver transplant recipients. USP19 overexpression mitigates post-transplant liver injury in mice. Mechanistically, USP19 inhibits the degradation of solute carrier family 7 member 11 (SLC7A11) by removing its K63-linked ubiquitin chains. Notably, USP19 overexpression reduces ferroptosis and IRI in a SLC7A11-dependent manner in mice. Collectively, USP19-mediated suppression of hepatocyte ferroptosis via deubiquitinating SLC7A11 is a key mechanism by which IFLT abrogates graft IRI.

Acute kidney injury (AKI) is one of the most common and severe clinical renal syndromes with high morbidity and mortality. Ferroptosis is a form of programmed cell death (PCD), is characterized by iron overload, reactive oxygen species accumulation, and lipid peroxidation. As ferroptosis has been increasingly studied in recent years, it is closely associated with the pathophysiological process of AKI and provides a target for the treatment of AKI. This review offers a comprehensive overview of the regulatory mechanisms of ferroptosis, summarizes its role in various AKI models, and explores its interaction with other forms of cell death, it also presents research on ferroptosis in AKI progression to other diseases. Additionally, the review highlights methods for detecting and assessing AKI through the lens of ferroptosis and describes potential inhibitors of ferroptosis for AKI treatment. Finally, the review presents a perspective on the future of clinical AKI treatment, aiming to stimulate further research on ferroptosis in AKI.

Hepatocellular carcinoma is one of the deadliest and fastest-growing cancers. Among HCC etiologies, metabolic dysfunction-associated fatty liver disease (MAFLD) has served as a major HCC driver due to its great potential for increasing cirrhosis. The obesogenic environment fosters a positive energy balance and results in a continuous rise of obesity and metabolic syndrome. However, it is difficult to understand how metabolic complications lead to the poor prognosis of liver diseases and which molecular mechanisms are underpinning MAFLD-driven HCC development. Thus, suitable preclinical models that recapitulate human etiologies are essentially required. Numerous preclinical models have been created but not many mimicked anthropometric measures and the course of disease progression shown in the patients. Here we review the literature on adipose tissues, liver-related HCC etiologies and recently discovered genetic mutation signatures found in MAFLD-driven HCC patients. We also critically review current rodent models suggested for MAFLD-driven HCC study.

Liver ischemia reperfusion (IR) injury significantly impacts clinical outcomes by increasing the risk of hepatic dysfunction after liver surgery. Fatty livers are more susceptible to IR stress. Recent studies have demonstrated that S100A9 plays a crucial role in both IR injury and the progression of liver steatosis. Nevertheless, the precise mechanisms underlying these effects remain unclear. In our study, transcriptome analysis of fatty livers subjected to IR insult in mice identified S100A9 as an important mediator. Employing loss-of-function approaches, we investigated the immune regulatory function of S100A9 and its downstream signaling in fatty liver IR injury. As expected, S100A9 emerged as one of the most significantly upregulated genes during the reperfusion stage in fatty livers. Genetic knockdown of S100A9 markedly ameliorated liver pathological damage, evidenced by reduced macrophage/neutrophil infiltration as well as the decreased expression of proinflammatory factors. Transcriptome/functional studies revealed that S100A9 triggered liver inflammatory response via regulating toll-like receptor 2 (TLR2)/activating transcription factor 4 (ATF4) signaling. Additionally, TLR2 expression was notably increased in macrophages from ischemic fatty livers. In vitro , recombinant S100A9-stimulated macrophages exhibited the elevated production of proinflammatory factors and TLR2/ATF4 pathway activation. Intriguingly, S100A9 facilitated ATF4 nuclear translocation and enhanced NEK7/NLRP3 inflammasome activation in macrophages. In conclusion, our study identified S100A9 as a key regulator responsible for macrophage NLRP3 inflammasome activation and subsequent inflammatory injury in fatty liver IR process. Targeting TLR2/ATF4 signaling may offer a novel therapeutic strategy for mitigating S100A9-mediated liver injury.

EFNA4, a member of the Ephrin-A ligand family, may influence hepatocellular carcinoma cells through two distinct mechanisms: one reliant on specific Eph receptor binding and the other independent of receptor involvement. However, EFNA4's influence on HCC via non-Eph receptor pathways remains unclear. In this study, we aimed to investigate the role of EFNA4 in a receptor-independent environment. Firstly, we constructed an environment lacking Eph receptors via CRISPR/Cas9 and found that EFNA4 could still partially promote HCC proliferation and metastasis in vivo and in vitro. Further analyses of apoptosis, ROS, and GPX4 expression revealed that overexpression of EFNA4 would inhibit ferroptosis in HCC. Mechanistically, EFNA4 was positively correlated with SLC7A11 and directly interacted with SLC7A11 in HCC via bioinformatics analysis. We demonstrated that the structural domain (a.a. 161-201) of EFNA4 specifically binds to the domain (a.a. 222-501) of SLC7A11, which led to the deubiquitination of SLC7A11. Subsequently, we found that EFNA4 would recruit the deubiquitinase USP9X, resulting in inhibition of SLC7A11 degradation, which ultimately inhibits ferroptosis and enhances the proliferation and metastasis of HCC. In conclusion, we demonstrated that EFNA4 promotes the proliferation and metastasis of HCC independent of Eph receptors by inhibiting ferroptosis and advancing the deubiquitination of SLC7A11 by recruiting the deubiquitinase USP9X. This indicates that EFNA4 could act as a potential prognostic marker and a prospective therapeutic target in patients with HCC.