Aging is a natural biological process that is characterized by the progressive decline in physiological functions and an increased vulnerability to age-related diseases. The aging process is driven by different cell and molecular mechanisms. It has recently been shown that aging is associated with heightened vulnerability to ferroptosis (an intracellular iron-dependent form of programmed cell death). This susceptibility arises from various factors including oxidative stress, impaired antioxidant defences, and dysregulated iron homeostasis. The progressive decline in cellular antioxidant capacity and the accumulation of damaged components contribute to the increased susceptibility of aging cells to ferroptosis. Dysregulation of key regulators involved in ferroptosis, such as glutathione peroxidase 4 (GPX4), iron regulatory proteins, and lipid metabolism enzymes, further exacerbates this vulnerability. The decline in cellular defence mechanisms against ferroptosis during aging contributes to the accumulation of damaged cells and tissues, ultimately resulting in the manifestation of age-related diseases. Understanding the intricate relevance between aging and ferroptosis holds significant potential for developing strategies to counteract the detrimental effects of aging and age-related diseases. This will subsequently act to mitigate the negative consequences of aging and improving overall health in the elderly population. This review aims to clarify the relationship between aging and ferroptosis, and explores the underlying mechanisms and implications for age-related disorders, including neurodegenerative, cardiovascular, and neoplastic diseases. We also discuss the accumulating evidence suggesting that the imbalance of redox homeostasis and perturbations in iron metabolism contribute to the age-associated vulnerability to ferroptosis.

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.

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.

Polyphyllin I (PPI), the primary active component extracted from the commonly utilized drug Paris polyphylla, in clinical applications, exhibits exceptional anti-tumor activity. Therefore, the objective of this study is to delve into its antitumor properties by promoting ferroptosis and enhancing anti-tumor immunity.

Our result demonstrate that PPI effectively suppresses the proliferation of NSCLC cells and triggers their demise through the induction of ferroptosis. Furthermore, the degradation of iron via autophagy is pivotal in mediating PPI-induced ferroptosis in NSCLC. Notably, EZH2 emerges as a potential key target of PPI, and its overexpression can significantly attenuate the therapeutic efficacy of PPI. Lastly, these mechanistic insights and pathways were corroborated in animal model, and we preliminarily revealing a stimulatory role of PPI in bolstering anti-tumor immunity.

PPI triggers ferroptosis in NSCLC by downregulating EZH2, promoting NCOA4/Ferritin mediated ferritinophagy, and enhances anti-tumor immunity by promoting CD8 +T infiltration into tumor tissue.

Melanoma is a devastating form of skin cancer characterized by a high mutational burden, limited treatment success, and dismal prognosis. Although immunotherapy and targeted therapies have significantly revolutionized melanoma treatment, the majority of patients fail to achieve durable responses, highlighting the urgent need for novel therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by the overwhelming accumulation of lipid peroxides, has emerged as a promising therapeutic approach in preclinical melanoma models. A deeper understanding of the ferroptosis landscape in melanoma based on its biology characteristics, including phenotypic plasticity, metabolic state, genomic alterations, and epigenetic changes, as well as the complex role and mechanisms of ferroptosis in immune cells could provide a foundation for developing effective treatments. In this review, we outline the molecular mechanisms of ferroptosis, decipher the role of melanoma biology in ferroptosis regulation, reveal the therapeutic potential of ferroptosis in melanoma, and discuss the pressing questions that should guide future investigations into ferroptosis in melanoma.

The term cardiomyopathy refers to a group of heart diseases that cause severe heart failure over time. Cardiomyopathies have been proven to be associated with ferroptosis, a non-apoptotic form of cell death. It has been shown that some small molecule drugs and active ingredients of herbal medicine can regulate ferroptosis, thereby alleviating the development of cardiomyopathy. This article reviews recent discoveries about ferroptosis, its role in the pathogenesis of cardiomyopathy, and the therapeutic options for treating ferroptosis-associated cardiomyopathy. The article aims to provide insights into the basic mechanisms of ferroptosis and its treatment to prevent cardiomyopathy and related diseases.

Toxoplasma gondii (T. gondii) is an intracellular parasite that extensively infects warm-blooded animals, causing toxoplasmosis and posing a significant threat to global public health. In this study, we investigated the association between T. gondii infection and ferroptosis in host cells, as well as the regulatory role of glutathione peroxidase 4 (GPX4). Our findings revealed that mice infected with RH and PRU strains of T. gondii exhibited significantly elevated levels of reactive oxygen species and malondialdehyde in brain and liver tissues. Concurrently, the expression of GPX4, a critical negative regulator of ferroptosis, was downregulated, which correlated with the elevated parasite burden. In Vero cells, T. gondii infection similarly inhibited GPX4 expression, whereas GPX4 overexpression suppressed T. gondii proliferation. These results indicate that T. gondii infection can promote ferroptosis in host cells and that GPX4 plays a pivotal role in regulating infection and proliferation. This study provides novel insights into the pathogenic mechanisms of T. gondii and identifies GPX4 as a regulatory factor that constrains parasite proliferation, offering new approaches for toxoplasmosis prevention and control.

Ferroptosis is implicated in various musculoskeletal conditions, including non-traumatic osteonecrosis of the femoral head (NT-ONFH).

The objective of this study was to explore the levels of two crucial proteins associated with ferroptosis, namely Glutathione peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11), in both serum and femoral head samples, and to correlate their expression levels with the clinical severity of NT-ONFH.

The study included 136 NT-ONFH patients and an equal number of healthy controls. In addition, 68 subjects suffering from femoral neck fractures (FNF) were included in the study. The serum concentrations of GPX4 and SLC7A11 were quantified using the enzyme-linked immunosorbent assay. The GPX4 and SLC7A11 levels among tissue samples were identified through immunohistochemical staining, western blot analysis, and quantitative real-time polymerase chain reaction (qRT-PCR). The radiographic severity of the condition was evaluated utilizing the Association Research Circulation Osseous (ARCO) classification system, while the symptomatic severity was assessed utilizing the Visual Analogue Scale (VAS) alongside the Harris Hip Score (HHS).

Patients diagnosed with NT-ONFH had considerably reduced serum concentrations of GPX4 and SLC7A11 in comparison to individuals in the healthy control group. Negative correlations of serum GPX4 and SLC7A11 levels with the ARCO stages were observed. A total of 73 ONFH and 68 FNF patients underwent total hip replacement. The mRNA and protein levels of GPX4 and SLC7A11 were lower in the necrotic areas compared to the non-necrotic areas and FNF femoral head tissues. Subsequent Receiver operating characteristic (ROC) curve analysis suggested that the decreased levels of both serum and local GPX4 and SLC7A11 could serve as potential biomarkers for the progression of ONFH. Furthermore, serum and local GPX4 and SLC7A11 levels were found to be negatively linked to the VAS score but positively related to the HHS score.

The levels of GPX4 and SLC7A11, both in serum and at the local site, were inversely correlated with the progression of NT-ONFH. Targeting ferroptosis and its associated proteins through potential therapeutic interventions could be a viable strategy to mitigate the severity of NT-ONFH.

Iron-based nanozymes are an emerging class of nanomaterials demonstrating significant potential in tumor therapy by inducing ferroptosis-a regulated form of cell death marked by iron-mediated lipid peroxidation (LPO). These nanozymes exhibit unique enzymatic activities, including peroxidase, oxidase, and glutathione oxidase-like functions, enabling them to generate reactive oxygen species (ROS) and disrupt tumor microenvironment homeostasis. Leveraging Fenton chemistry, iron-based nanozymes amplify oxidative stress within tumor cells, thereby overcoming therapeutic challenges such as drug resistance and nonspecific toxicity. Despite significant advancements, the precise mechanisms by which iron-based nanozymes influence ferroptosis and their therapeutic efficacy remain underexplored. This review systematically categorizes these iron-based nanozymes, including iron oxides, single-atom enzymes, and metal-organic frameworks. We further elucidate their mechanisms in enhancing ferroptosis, focusing on their structural attributes, ROS generation pathways, and their enzymatic activities. Additionally, we summarized their biochemical applications alongside challenges in biosafety, nanozyme specificity, and advanced design and analysis approaches essential for maximizing their therapeutic efficacy.

The discovery and conceptualization of ferroptosis as regulated, iron-catalyzed cell death driven by excessive lipid peroxidation triggered re-evaluation of lipid hydroperoxides in connection with health and disease. Free and ester forms of polyunsaturated fatty acids (PUFAs) are oxidized in vivo by multiple oxidizing species to produce lipid hydroperoxides as primary products, some purposely while others unintentionally. The detailed analysis of isomer distribution of lipid hydroperoxides enables us to identify the responsible oxidants. Linoleates, the most abundant PUFA in humans, are oxidized to give multiple isomers of hydroperoxyoctadecadienoates (H(p)ODEs) as primary major products, racemic trans, trans-9- and 13-H(p)ODEs, 13(S)-cis, trans-H(p)ODE, and 10- and 12-H(p)ODEs being specific biomarker for the oxidation by free radicals, lipoxygenase (LOX), and singlet oxygen, respectively. Cholesterol is another important lipid and its hydroperoxides are produced solely by non-enzymatic oxidation, the major products being cholesterol 7-hydroperoxide and 5-hydroperoxide by free radicals and singlet oxygen, respectively. The available data obtained from human samples show that lipid hydroperoxides are produced in vivo primarily by free radical mediated lipid peroxidation and that the contribution of LOXs s and singlet oxygen is small. Multiple antioxidants having different functions play their respective roles in the physiological defense network against detrimental lipid peroxidation and ferroptosis. The fact that lipid hydroperoxides are produced in vivo mainly by free radical mediated lipid peroxidation suggests that radical scavenging antioxidants act as essential ferroptosis inhibitors, which was substantiated by many studies. Considering the reactivity and physiological concentrations, it may be said that vitamins E and C play the primary roles as biological radical scavenging antioxidants against ferroptosis by synergistic interactions. Novel synthetic antioxidants with higher reactivity than natural antioxidants have been reported and their biological effects should be assessed. The factors that determine antioxidant effects in vivo are critically reviewed.

Ferroptosis, a form of regulated cell death associated with glutathione depletion and excess lipid peroxidation, can be induced in cultured cells by chemicals (e.g., erastin and RSL3). It has been shown that protein disulfide isomerase (PDI) is a mediator of chemically-induced ferroptosis and also a crucial target for ferroptosis protection. The present study reports that bazedoxifene (BAZ), a selective estrogen receptor modulator, is an inhibitor of PDI and can strongly rescue neuronal cells from chemically-induced oxidative ferroptosis. We find that BAZ can directly bind to PDI and inhibit its catalytic activity. Computational modeling analysis reveals that BAZ forms a hydrogen bond with PDI's His256 residue. Inhibition of PDI by BAZ markedly reduces iNOS and nNOS dimerization (i.e., catalytic activation) and NO accumulation, and these effects of BAZ are associated with reductions in cellular ROS and lipid-ROS and protection against chemically-induced ferroptosis. In addition, the direct antioxidant activity of BAZ may also partially contribute to its protection against chemically-induced ferroptosis. In vivo animal experiments show that mice treated with BAZ are strongly protected against kainic acid-induced oxidative hippocampal neuronal injury and memory deficits. Together, these results reveal that BAZ is a potent inhibitor of PDI and can strongly protect against chemically-induced ferroptosis in hippocampal neurons both in vitro and in vivo. This work provides evidence for an estrogen receptor-independent, PDI-mediated novel mechanism of neuroprotection by BAZ.

Accurately recognizing and regulating the transition time of macrophages to a pro- (M1-like) or anti-inflammatory (M2-like) state is essential for improving chronic inflammation in pressure injuries (PIs).

This study aimed to evaluate the effectiveness of infrared thermography (IRT) in measuring wound temperature of PIs for the purpose of guiding treatment in regulating chronic inflammation.

The healing process of 21 patients with PIs was monitored using IRT prospectively followed for 30 days. The wound temperature changing pattern of different healing outcomes were analyzed and calculated the optimal wound temperature range to guide the treatment time of anti-inflammation for 100 patients with PIs accurately. Additionally, the molecular mechanisms underlying the observed temperature changes in a mouse model of PI were investigated, and the effect of IRT-guided chronic inflammation targeting ferroptosis modulation on PIs was validated.

The application of IRT to monitor PIs temperatures outside the 36.23 °C to 37.37 °C range is indicative of a potential risk indicator, which allows for the timely guidance of treatment to markedly enhance the efficacy of PIs healing outcomes. This wound temperature change was also observed during the process of PIs healing in mice, as a result of the imbalance of M1-like/M2-like macrophages and the subsequent chronic inflammation. Mechanically, evidence indicates that ferroptosis is hyperactivated in PIs, and the enrichment of M1-like macrophages with iNOS/NO• can enhance their resistance to ferroptosis compared with M2-like macrophages, resulting in the imbalance of M1-like/M2-like macrophages and subsequent alteration of wound temperature.

The modulation of M2-like macrophage resistance to ferroptosis in PIs by NO• donors, suggesting by IRT-monitored temperature changes, has been demonstrated to significantly improve chronic inflammation. This establishes a foundation for the application of IRT to direct a therapeutic strategy for the precise promotion of PIs healing.

Cerebral ischemia/reperfusion injury (CIRI) is a critical factor leading to adverse outcomes in acute ischemic stroke with reperfusion therapy. The occurrence of CIRI involves several cell death pathways, such as ferroptosis. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) a vital role in mitochondrial biogenesis and induces several crucial reactive oxygen species (ROS) detoxifying enzymes. Nonetheless, the role of activated PGC-1α in CIRI is still unclear. In this research, we utilized a PGC-1α agonist (ZLN005) in both in vitro and in vivo models of CIRI and found that ZLN005 ameliorates neurologic deficits, reduces infarct volume, and inhibits neuronal ferroptosis in CIRI. Furthermore, CIRI led to a decrease in neuronal mitochondrial quantity and downregulation of uncoupling protein 2 (UCP2) expression. Treatment with ZLN005 activated PGC-1α, promoted neuronal mitochondrial biogenesis, and upregulated UCP2 expression, thereby reducing mitochondrial oxidative stress. The application of the mitochondria-targeted antioxidant Mito-TEMPO inhibited ferroptosis, while UCP2 silencing induced mitochondrial oxidative stress and weakened ZLN005 inhibitory effect of ferroptosis, confirming the dependency of ferroptosis on mitochondrial oxidative stress in CIRI. According to these findings, targeting PGC-1α may offer an effective therapeutic strategy for CIRI by regulating mitochondrial homeostasis and protecting neurons from ferroptotic damage.

With the global population aging, musculoskeletal disorders (MSDs) have posed significant physical and psychological health challenges for patients as well as a substantial economic burden on society. The advancements in conservative and surgical interventions for MSDs have been remarkable in recent years; however, the current treatment modalities still fall short of meeting the optimal requirements of patients. Recently, peroxiredoxin 6 (Prdx6) has gained considerable attention from researchers due to its remarkable antioxidative, anti-inflammatory, and anti-apoptotic properties. It has been found that Prdx6 is involved in multiple system diseases, including MSDs; however, the exact role of Prdx6 in MSDs is still lacking. This study aimed to summarize the structure, regulatory mechanism, and potential function of Prdx6. These findings may demonstrate Prdx6 as a novel target for inhibiting the advancement of MSDs.

Ferroptosis, a form of cell death instigated by iron-dependent lipid peroxidation reactions (LPO), is emerging as a promising therapeutic target for cancer. While the mechanisms governing LPO induction and suppression have gradually been unveiled, questions persist regarding the specific cellular location of LPO and the utilization of iron in driving cell death. A comprehensive understanding of these aspects holds significant potential for advancing therapeutic applications in disease management. Here, we show lysosomal LPO in the initiation of ferroptosis, leveraging the hidden abilities of fluorescent detection probes. Intra-lysosomal LPO triggers iron leakage, fostering cell-wide LPO by augmenting lysosomal membrane permeabilization (LMP). Conversely, cell lines with low susceptibility to ferroptosis do not exhibit LMP. This deficiency is rectified by the concurrent administration of chloroquine, leading to LMP induction and subsequent cell death. These findings underscore enhancing LMP induction efficacy as a strategic approach to surmount resistance to therapies in cancer.

Apatinib is a targeted therapy used in the treatment of advanced gastric cancer. However, many gastric cancer patients develop resistance to Apatinib, and the mechanisms underlying this resistance remain unclear. Previous studies have shown that Apatinib can induce ferroptosis in gastric cancer cells. More recent research suggests that polyunsaturated ether phospholipids are closely associated with tumor cell sensitivity to ferroptosis, and may represent key molecules involved in the resistance of tumor cells to ferroptosis.

We established Apatinib-resistant gastric cancer cell lines and assessed their tolerance to ferroptosis. We identified key enzymes responsible for the ferroptosis tolerance observed in drug-resistant cells using lipidomics and transcriptomics analysis. Molecular and biological experiments were conducted to elucidate the molecular mechanisms underlying Apatinib resistance mediated by ferroptosis tolerance in gastric cancer cells.

Apatinib resistance is closely linked to ferroptosis resistance, which is driven by a reduction in the levels of polyunsaturated ether phospholipids-phospholipids that are particularly susceptible to oxidation and induce ferroptosis. The downregulation of key enzymes involved in polyunsaturated ether phospholipid synthesis, such as AGPS, mediates tolerance to both ferroptosis and Apatinib in gastric cancer cells, both in vitro and in vivo. Mechanistically, the expression of AGPS in tumor cells is regulated by the transcription factor ELK1. Drug-resistant cells acquire Apatinib tolerance by downregulating both ELK1 and AGPS expression.

Apatinib-resistant gastric cancer cells exhibit reduced expression of the transcription factor ELK1, which regulates the expression of AGPS. This reduction contributes to the resistance and malignancy of gastric cancer cells.

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).

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical factor in female reproductive health and has been implicated in disorders such as polycystic ovary syndrome, premature ovarian insufficiency, endometriosis, and ovarian cancer. This review explores the intricate molecular mechanisms underlying ferroptosis, emphasizing its reliance on iron metabolism and oxidative stress, which disrupt key processes in reproductive tissues, including granulosa cell function, folliculogenesis, and embryo implantation. Increasing evidence linking ferroptosis to these conditions offers new therapeutic opportunities, with iron chelators, lipid peroxidation inhibitors, and antioxidants showing the potential to alleviate reproductive dysfunction by modulating ferroptotic pathways. In ovarian cancer, ferroptosis inducers combined with conventional cancer therapies, such as chemotherapy, provide promising strategies to overcome drug resistance. This review synthesizes current knowledge on ferroptosis and highlights its importance as a therapeutic target in reproductive health, emphasizing the need for further research to refine and expand treatment options, evaluate their applicability in clinical settings, and explore their role in fertility preservation. By advancing our understanding of ferroptosis regulation, these therapeutic approaches could lead to novel treatments for reproductive disorders and cancers, offering new hope for improving outcomes in women's health and cancer therapy.

Ferroptosis is a unique regulated form of cell death that is distinct from apoptosis, necrosis, and other well-characterized regulated cell death types, and plays an important role in the occurrence and development of chronic metabolic diseases, including diabetes, hypertension, hyperlipidemia, and non-alcoholic steatohepatitis. Recently, increasing evidence has supported traditional Chinese medicine (TCM) as a new hot spot for the treatment of chronic metabolic diseases by mediating ferroptosis. Unfortunately, few systematic reviews have described the importance of TCM in treating chronic metabolic diseases through the ferroptosis pathway. In the current review, the mechanism of ferroptosis and the roles of ferroptosis in chronic metabolic diseases are summarized. Additionally, this review illustrates that the regulation of ferroptosis by TCM could be an effective approach for treating chronic metabolic diseases based on experimental evidence and clinical application. In summary, this work will improve the understanding of ferroptosis and the ability of TCM to regulate ferroptosis in chronic metabolic diseases, thereby promoting the development and application of natural TCM.

Ferroptosis, a regulated form of cell death, is characterized by iron accumulation that results in the production of reactive oxygen species. This further causes lipid peroxidation and damage to the cellular components, eventually culminating into oxidative stress. Recent studies have highlighted the pivotal role of ferroptosis in the pathophysiological development and progression of various diseases such as β-thalassemia, hemochromatosis, and neurodegenerative disorders like AD and PD. Extensive efforts are in progress to understand the molecular mechanisms governing the role of ferroptosis in these conditions, and chelation therapy stands out as a potential approach to mitigate ferroptosis and its related implications in their development. There are currently both synthetic and natural iron chelators that are being researched for their potential as ferroptosis inhibitors. While synthetic chelators are relatively well-established and studied, their short plasma half-life and toxic side effects necessitate the exploration and identification of natural products that can act as efficient and safe iron chelators. In this review, we comprehensively discuss both synthetic and natural iron chelators as potential therapeutic strategies against ferroptosis-induced pathologies.

Ferroptosis, a form of oxidative cell death mediated by lipid peroxidation, is strictly regulated by glutathione peroxidase 4 (GPX4). Knockout of Gpx4 results in embryonic lethality, highlighting its essential role in development. In vitro, mouse embryonic stem cells (mESCs), which represent the naïve pluripotent state, require β-mercaptoethanol (bME) to prevent cell death, unlike human embryonic stem cells, which represent the primed state. We hypothesized that naïve pluripotency is linked to a heightened susceptibility to ferroptosis due to unique metabolic demands and redox imbalances. In this study, we found that bME deprivation induces ferroptosis in naïve ESCs, as evidenced by lipid peroxidation; ferroptosis, however, is less evident in primed ESCs. Mechanistic analyses revealed that active oxidative phosphorylation (OXPHOS) in naïve ESCs increased mitochondrial reactive oxygen species. Consistent with the upregulation of Gpx4 transcripts and OXPHOS-associated gene sets seen in the inner cell mass of blastocysts, stable GPX4 expression conferred resistance to ferroptosis induced by bME withdrawal. These results suggest that the unique redox and metabolic landscape of naïve ESCs highlits a potential requirement for GPX4 in maintaining naïve pluripotency, providing insights into early developmental processes and vulnerabilities.

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular event associated with high mortality and significant morbidity. Recent studies have highlighted the emerging role of ferroptosis, a novel form of regulated cell death, in the pathogenesis of SAH. Circular RNAs (circRNAs), have been found to play essential roles in various cellular processes, including gene regulation and disease pathogenesis. The expression profile of circRNAs in neural tissues, particularly in the brain, suggests their critical role in synaptic function and neurogenesis. Moreover, the interplay between circRNAs and ferroptosis-related pathways, such as iron metabolism and lipid peroxidation, is explored in the context of SAH. Understanding the functional roles of specific circRNAs in the context of SAH may provide potential therapeutic targets to attenuate ferroptosis-associated brain injury. Furthermore, the potential of circRNAs as diagnostic biomarkers for SAH severity, prognosis, and treatment response is discussed. Overall, this review highlights the significance of studying the intricate interplay between circRNAs and ferroptosis in the context of SAH. Unraveling the mechanisms by which circRNAs modulate ferroptotic cell death may pave the way for the development of novel therapeutic strategies and diagnostic approaches for SAH management, ultimately improving patient outcomes and quality of life.

Cancer is the main leading cause of death worldwide and poses a great threat to human life and health. Although pharmacological treatment with chemotherapy and immunotherapy is the main therapeutic strategy for cancer patients, there are still many shortcomings during the treatment such as incomplete killing of cancer cells and development of drug resistance. Emerging evidence indicates the promise of inducing ferroptosis for cancer treatment, particularly for eliminating aggressive malignancies that are resistant to conventional therapies. This review covers recent advances in important regulatory targets in the ferroptosis metabolic pathway and ferroptosis inducers (focusing mainly on the last 3 years) to delineate their design, mechanisms of action, and anticancer applications. To date, many compounds, including inhibitors, degraders, and active molecules from traditional Chinese medicine, have been demonstrated to have ferroptosis-inducing activity by targeting the different biomolecules in the ferroptosis pathway. However, strictly defined ferroptosis inducers have not yet been approved for clinical use; therefore, the discovery of new highly active, less toxic, and selective compounds remains the goal of further research in the coming years.

In drug development, systematically characterizing a compound's mechanism of action (MoA), including its direct targets and effector proteins, is crucial yet challenging. Network-based approaches, unlike those focused solely on direct targets, effectively detect a wide range of cellular responses elicited by compounds. This study applied protein covariation network analysis, leveraging quantitative, morphological, and localization features from immunostained microscopic images, to elucidate the MoA of AX-53802, a novel ferroptosis inducer. From the candidate targets extracted through network analysis, GPX4 was verified as the direct target by validation experiments. Additionally, aggregates involving GPX4, TfR1, and F-actin were observed alongside iron reduction, suggesting a ferroptosis defense mechanism. Furthermore, combination therapies targeting GPX4 and FAK/Src were found to enhance cancer cell death, and MDM2, ezrin, and cortactin were identified as potential ferroptosis inhibitor targets. These findings highlight the effectiveness of network-based approaches in uncovering a compound's MoA and developing combination therapies for cancer.

This study aimed to investigate the neuroprotective potential of the tetracycline (TC) antibiotic oxytetracycline (OT) and its non-antibiotic derivative 4-dedimethylamino 12a-deoxy-oxytetracycline (DOT), in experimental conditions that mimic the gradual loss of dopamine (DA) neurons in Parkinson's disease (PD). Specifically, we established a model system of mouse midbrain cultures where DA neurons progressively die when exposed to an iron-containing medium. We found that OT (EC50 = 0.25µM) and DOT (EC50 = 0.34µM) efficiently protected DA neurons from degeneration, with these effects observable until advanced stages of neurodegeneration. The reference antibiotic TC doxycycline (DOX) also exhibited protective effects in this context. Importantly, DA neurons rescued by OT, DOT, and DOX retained their capacity to accumulate and release DA, indicating full functional integrity. Additionally, molecules with iron-chelating properties (apotransferrin, desferoxamine), as well as inhibitors of lipid peroxidation and ferroptosis (Trolox, Liproxstatin-1), could replicate the rescue of DA neurons provided by OT, DOT, and DOX. Live-cell imaging studies showed that test TCs and other neuroprotective molecules prevented the emission of intracellular reactive oxygen species and the associated disruption of the mitochondrial membrane potential. However, neither OT, DOT, nor DOX could protect DA neurons from selective mitochondrial poisoning by 1-methyl-4-phenylpyridinium. This suggests that test TCs may be protective against iron-mediated damage through a mechanism not directly involving mitochondria. Overall, we demonstrate that OT and DOT possess promising properties that could be useful for combating PD neurodegeneration. However, the absence of antimicrobial activity makes DOT a better candidate drug compared to its parent compound OT.

The core syndrome among NBIA disorders is pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder caused by mutations in the PANK2 gene. There is no therapy for PKAN; only symptomatic treatment is available. Our work aimed to identify the mechanisms induced by biochemical disturbances in the cell cycle and identify potential pharmacological targets to improve patient quality of life. Mass spectrometry (MS) (metals) and NMR spectroscopy (hydrophilic and hydrophobic compounds) were used for profile analyses of the sera of 12 PKAN patients and 12 controls to study the compounds involved in PKAN pathomechanisms. We performed ANOVA and multivariate analysis using orthogonal partial least squares discriminant analysis. We have shown for the first time that patients have 100-500-fold greater serum citrate levels than controls do, which may contribute to Fe transport and ferroptosis. Ferroptosis may be indicated by disturbances in the levels of many metals, oxidative stress, disturbances in energy production and neurotransmission or dysfunction of biological membranes. Our findings suggest that ferroptosis could be a primary cause of cell death in PKAN patients. This could be indicated by serum metabolomics.

Radioresistance is a major challenge in tumor radiotherapy and involves in a mixture of cellular events, including ferroptosis, a new type of programmed cell death characterized by the excess accumulation of iron-dependent lipid peroxides. In the present study, we observed that surviving cancer tissues and cells after radiotherapy had significantly greater glutathione to oxidized glutathione (GSH/GSSG) ratios and lower lipid reactive oxygen species (ROS) and malondialdehyde (MDA) levels than nonirradiated tumors and cells. Untargeted lipidomic analyses revealed that oleic acid (OA) and palmitoleic acid (POA) were the most significantly upregulated unsaturated fatty acids in irradiated surviving cancer cells compared with those in control cancer cells irradiated with IR. Both OA and POA could protect cancer cells from the killing effects of the ferroptosis inducer erastin and RSL3, and OA had a stronger protective effect than POA, resulting in lower lipid ROS production than POA. Mechanistically, OA protected cells from ferroptosis caused by the accumulation of polyunsaturated fatty acid-containing phospholipids in an ACSL3-dependent manner. A mouse model demonstrated that ACSL3 knockdown combined with imidazole ketone erastin synergistically enhanced antitumor effects in radiation-resistant tumors in vivo. Our study reveals previously undiscovered associations between radiation and fatty acid metabolism and ferroptosis, providing a novel treatment strategy for overcoming cancer radioresistance.

Among the most common malignant tumors, hepatocellular carcinoma (HCC) is a primary liver cancer type that has a high mortality rate. HCC often presents insidiously, is prone to recurrence, and has limited treatment efficacy. Ferroptosis regulates tumorigenesis, progression, and metastasis, which is a novel form of iron-dependent cell death. Numerous studies suggest that HCC is sensitive to ferroptosis, indicating that targeted therapies aimed at inducing ferroptosis may represent a promising new approach to cancer treatment. This study aims to find genes associated with HCC and ferroptosis, as well as to screen for potential agents that may cause ferroptosis in HCC. Transcriptome and clinical sample data were obtained from the TCGA database to identify differentially expressed genes related to ferroptosis. Using various regression and survival analysis techniques, we developed a prognostic model based on four core genes and evaluated its predictive potential. Subsequently, we screened for potential therapeutic agents in the Connective Map (CMap) database, designated as compound Atorvastatin, based on differential genes from two risk groups and related to ferroptosis. Through experiments conducted in vivo and in vitro, we demonstrated that Atorvastatin can induce ferroptosis in HCC cells while inhibiting their growth and migration. In conclusion, this research targets ferroptosis therapy and provides new insights for improving the prediction and prevention of HCC.

Atherosclerosis (AS) is a chronic inflammatory disease caused by the dysregulation of lipid metabolism. It has been established that oxidized low-density lipoprotein (ox-LDL)-induced macrophage inflammation and ferroptosis play important roles in AS. However, the mechanism by which ox-LDL induces inflammation in macrophages requires further investigation.

A foam cell model derived from ox-LDL-induced macrophages was constructed to study its mechanism of action. The levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were evaluated using an Enzyme-Linked Immunosorbent Assay (ELISA). Oil Red O staining was used to detect intracellular lipid accumulation levels. Lactate dehydrogenase (LDH), malondialdehyde (MDA), reactive oxygen species (ROS), and Fe2+ levels were assessed. Dual-luciferase and RNA-binding protein immunoprecipitation (RIP) experiments validated the binding relationship between microRNA (miR)-214-3p and glutathione peroxidase 4 (GPX4).

The levels of IL-6, IL-1β, and TNF-α were significantly increased in ox-LDL-induced macrophages, accompanied by increased lipid accumulation, indicating the promotion of foam cell formation. Additionally, ox-LDL increased LDH, MDA, ROS, and Fe2+. The expression of miR-214-3p positively correlated with ox-LDL concentration in macrophages. Treatment with an miR-214-3p inhibitor reduces lipid accumulation, inflammatory responses, and ferroptosis in macrophages. Dual-luciferase and RIP experiments confirmed that miR-214-3p regulates GPX4 transcription. Silenced GPX4 reversed the inflammatory effects of the miR-214-3p inhibitor on ox-LDL-induced macrophages. Low GPX4 expression also increased lipid accumulation and ferroptosis in macrophages.

miR-214-3p promotes macrophage ferroptosis and inflammation induced by ox-LDL. This mechanism may be associated with miR-214-3p-induced GPX4 expression, which underscores the therapeutic significance of targeting macrophage inflammation and ferroptosis in addressing AS.

In recent 10 years, ferroptosis has become a hot research direction in the scientific research community as a new way of cell death. Iron toxicity accumulation and lipotoxicity are unique features. Several studies have found that ferroptosis is involved in the regulation of the hepatic microenvironment and various hepatic metabolisms, thereby mediating the progression of related liver diseases. For example, NRF2 and FSP1, as important regulatory proteins of ferroptosis, are involved in the development of liver tumors and liver failure. In this manuscript, we present the mechanisms involved in ferroptosis, the concern of ferroptosis with the liver microenvironment and the progression of ferroptosis in various liver diseases. In addition, we summarize recent clinical advances in targeted ferroptosis therapy for related diseases. We expect that this manuscript can provide a new perspective for clinical treatment of related diseases.

Ferroptosis, a regulated form of cell death characterized by lipid peroxidation and iron accumulation, is increasingly recognized for its role in disease pathogenesis. The unfolded protein response (UPR) has been implicated in both endoplasmic reticulum (ER) stress and ferroptosis-mediated cell fate decisions; yet, the specific mechanism remains poorly understood. In this study, we demonstrated that ER stress induced by tunicamycin and ferroptosis triggered by erastin both activate the UPR, leading to the induction of ferroptotic cell death. This cell death was mitigated by the application of chemical chaperones and a ferroptosis inhibitor. Among the three arms of the UPR, the PERK-eIF2α-ATF4 signaling axis was identified as a crucial mediator in this process. Mechanistically, the ATF4-driven induction of DDIT4 plays a pivotal role, facilitating ferroptosis via the inhibition of the mTORC1 pathway. Furthermore, acetaminophen (APAP)-induced hepatotoxicity was investigated as a model of eIF2α-ATF4-mediated ferroptosis. Our findings reveal that the inhibition of eIF2α-ATF4 or ferroptosis protects against APAP-induced liver damage, underscoring the therapeutic potential of targeting these pathways. Overall, this study not only clarifies the intricate role of the PERK-eIF2α-ATF4 axis in ER-stress-and erastin-induced ferroptosis but also extends these findings to a clinically relevant model, providing a foundation for potential therapeutic interventions in conditions characterized by dysregulated ferroptosis and ER stress.

Ferroptosis, a regulated form of cell death characterized by excessive iron-dependent lipid peroxidation, can be readily induced in cultured cells by chemicals such as erastin and RSL3. Protein disulfide isomerase (PDI) has been identified as an upstream mediator of chemically induced ferroptosis and also a target for ferroptosis protection. In this study, we discovered that raloxifene (RAL), a selective estrogen receptor modulator known for its neuroprotective actions in humans, can effectively inhibit PDI function and provide robust protection against chemically induced ferroptosis in cultured HT22 neuronal cells. Specifically, RAL can bind directly to PDI both in vitro and in intact neuronal cells and inhibit its catalytic activity. Computational modeling analysis reveals that RAL can tightly bind to PDI through forming a hydrogen bond with its His256 residue, and biochemical analysis further shows that when PDI's His256 is mutated to Ala256, RAL loses its inhibition of PDI's catalytic activity. This inhibition of PDI by RAL significantly reduces the dimerization of both the inducible and neuronal nitric oxide synthases and the accumulation of nitric oxide, both of which have recently been shown to play a crucial role in mediating chemically induced ferroptosis through subsequent induction of ROS and lipid-ROS accumulation. In vivo behavioral analysis shows that mice treated with RAL are strongly protected against kainic acid-induced memory deficits and hippocampal neuronal damage. In conclusion, this study demonstrates that RAL is a potent inhibitor of PDI and can effectively prevent chemically induced ferroptosis in hippocampal neurons both in vitro and in vivo. These findings offer a novel estrogen receptor-independent mechanism for RAL's neuroprotective actions in animal models and humans.

Osteoporosis (OP) is a common disease in the elderly, characterized by decreased bone strength, reduced bone density, and increased fracture risk. There are two clinical types of osteoporosis: primary osteoporosis and secondary osteoporosis. The most common form is postmenopausal osteoporosis, which is caused by decreased estrogen production after menopause. Secondary osteoporosis, on the other hand, occurs when certain medications, diabetes, or nutritional deficiencies lead to a decrease in bone density. Ferroptosis, a new iron-dependent programmed cell death process, is critical in regulating the development of osteoporosis, but the underlying molecular mechanisms are complex. In the pathologic process of osteoporosis, several studies have found that ferroptosis may occur in osteocytes, osteoblasts, and osteoclasts, cell types closely related to bone metabolism. The imbalance of iron homeostasis in osteoblasts and excessive iron accumulation can promote lipid peroxidation through the Fenton reaction, which induces ferroptosis in osteoblasts and affects their role in regulating bone metabolism. Ferroptosis in osteoblasts inhibits bone formation and reduces the amount of new bone production. Osteoclast-associated ferroptosis abnormalities, on the other hand, may alter the homeostasis of bone resorption. In this paper, we start from the molecular mechanism of ferroptosis, and introduce the ways in which ferroptosis affects the physiological and pathological processes of the body. After that, the effects of ferroptosis on osteoblasts and osteoclasts will be discussed separately to elucidate the molecular mechanism between ferroptosis and osteoporosis, which will provide a new breakthrough for the prevention and treatment of osteoporosis and a more effective and better idea for the treatment strategy of osteoporosis.

Parkinson's disease (PD), a common neurodegenerative disorder, is characterized by progressive loss of dopaminergic neurons, and accumulation of α-synuclein in the substantial nigra. Emerging evidence identifies ferroptosis as a regulated iron-dependent cell death mechanism marked by excessive lipid peroxidation (LPO) as a key contributor to PD pathogenesis. Ferroptosis is intertwined with critical disease processes such as aggregation of α-synuclein protein, oxidative stress generation, mitochondrial alteration, iron homeostasis dysregulation, and neuroinflammation. This mechanism disrupts cellular homeostasis by impairing iron metabolism and antioxidant pathways like the xc-/glutathione/GPX4 axis and the CoQ10 pathway. This review consolidates current advancements in understanding ferroptosis in these mechanisms, increasing interest in contribution to PD pathology. In addition, it explores the latest developments in ferroptosis-targeting pharmacological agents, including their application in the preclinical and clinical study, and highlights their potential to revolutionize PD management. Unraveling the interplay between ferroptosis and PD offers a transformative perspective, paving the way for innovative therapies to combat this debilitating disease condition.

Iron is an essential micronutrient for cell survival and growth; however, excess of this metal drives ferroptosis. Although maternal iron imbalance and placental hypoxia are independent contributors to the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy, the mechanisms by which their interaction impinge on maternal and placental health remain elusive.

We used placentae from normotensive and preeclampsia pregnancy cohorts, human H9 embryonic stem cells differentiated into cytotrophoblast-like cells, and placenta-specific Phd2-/- preeclamptic mice. Lipid peroxidation and iron cargo of placenta-derived small extracellular vesicles (sEVs) isolated from the maternal circulation of control and preeclampsia individuals were examined by mass spectrometry, flow cytometry, and colorimetry. Human microvascular endothelial cells' angiogenic capacity and function were examined after exposure to control and pathological sEVs.

Placentae from preeclampsia pregnancies contain increased ferrous iron and lipid peroxidation byproduct, malondialdehyde. Antioxidant capacity is significantly lower in preeclampsia placentae, with decreased glutathione content, and GPx4 (glutathione peroxidase 4) expression and activity. Hypoxia triggers the occurrence of ferroptosis in human trophoblast cells and mouse Phd2-/-placentae. Disrupted placental iron homeostasis in preeclampsia is accompanied by improper extrusion of iron through sEVs mediated by the pentaspan protein prominin-2. Heightened lipid peroxidation content was found in villous explants and maternal circulating sEVs of preeclampsia individuals. Exposure of human microvascular endothelial cells to preeclampsia-derived placental sEVs results in endothelial activation and impaired angiogenesis, which is rescued by treatment with hinokitiol, a compound known to restore tissue iron balance.

In pregnancy, iron and oxygen work synergistically to conserve an operative antioxidant system to maintain iron homeostasis and protect the placenta from ferroptotic death. Hindrance to this system due to hypoxia results in heightened ferroptosis rates and sEV-mediated extrusion of harmful lipid peroxides from trophoblast cells into the circulation thereby contributing to maternal endothelial dysfunction characterizing preeclampsia.

To unveil the efficacy and ferroptosis-related mechanisms of Atractylodes Macrocephala Koidz (AMK) against Alzheimer's disease (AD), which is the most widespread neurodegenerative disease.

Gene set variation analysis (GSVA) scores were used to investigate the relationship between ferroptosis and AD. Logistic regression with seven feature selections and a deep learning model were utilized to identify potential targets of AMK based on transcriptomic data from multiple tissues. A transcriptome-wide association study (TWAS), summary-data-based mendelian randomization (SMR), and mendelian randomization (MR) were utilized to validate the causal relationship between target genes and AD risk. A single-gene gene set enrichment analysis (GSEA) was employed to investigate the biological pathways associated with the target genes. Three molecular docking strategies and a molecular dynamics simulation were employed to verify the binding domains interacting with AMK. Furthermore, the anti-AD effects of AMK were validated in a zebrafish AD model by testing behavior responses, apoptosis, and the deposition of beta-amyloid (Aβ) in the brain. Ultimately, real-time qPCR was used to verify the ferroptosis-related targets, which was identified via multi-omics.

Ferroptosis is an important pathogenic mechanism of AD, as suggested by the GSVA scores. AMK may exert its anti-AD activity through targets genes identified in the brain (ATP5MC3, GOT1, SAT1, EGFR, and MAPK9) and blood (G6PD, PGD, ALOX5, HMOX1, and ULK1). EGFR and HMOX1 were further confirmed as target genes mediating the anti-AD activity of AMK through TWAS, SMR, and MR analyses. The GSEA results indicated that EGFR may be involved in oxidative phosphorylation-related pathways, while HMOX1 may be associated with lysosome and phagosome pathways. The results of three molecular docking strategies and molecular dynamics simulations implied that the kinase domain of EGFR and the catalytic domain of HMOX1 played pivotal roles in the interaction between AMK and the targets. In a zebrafish model, AD-like symptoms including motor slowness and delayed responses, neuronal apoptosis, and plaque deposition in the brain, were significantly improved after AMK treatment. Accordingly, AMK reversed the abnormal expression of egfra and hmox1a, two core targets genes involved in ferroptosis.

AMK significantly alleviated AD-like symptoms through the modulation of EGFR and HMOX1, which might reduce lipid peroxidation, thereby suppressing ferroptosis. This study provided evidence supporting the efficacy and therapeutic targets associated with ferroptosis in AMK-treated AD, which aid in the development of therapeutic interventions.

Small molecule modulators are powerful tools for selectively probing and manipulating proteins in native biological systems. However, the development of versatile modulators that exhibit desired properties is hindered by the lack of a rapid and robust synthetic strategy. Here, we develop a facile and reliable one-step methodology for the generation of multifunctional toolboxes encompassing a wide variety of chemical modulators with different desired features. These modulators bind irreversibly to the protein target via a selective warhead. Key elements are introduced onto the warhead in a single step using multi-component reactions. To illustrate the power of this new technology, we synthesized a library of diverse modulators designed to explore a highly challenging and poorly understood protein, human 15-lipoxygenase-1. Modulators made include; activity-based/photoaffinity probes, chemosensors, photocrosslinkers, as well as light-controlled and high-affinity inhibitors. The efficacy of our compounds was successfully established through the provision of on demand inhibition and labeling of our target protein in vitro, in cellulo and in vivo; thus, proving that this technology has promising potential for applications in many complex biological systems.