Glutathione (GSH), a non-enzymatic antioxidant in mammalian cells, plays an essential role in maintaining redox balance, mitigating oxidative stress, and preserving cellular homeostasis. Beyond its well-established function in detoxifying reactive oxygen species (ROS), GSH serves as a critical regulator of ferroptosis-an iron-dependent form of cell death marked by excessive lipid peroxidation. Serving as a cofactor for glutathione peroxidase 4 (GPX4), GSH catalyzes the conversion of lipid peroxides into non-toxic lipid alcohols, thereby preventing the accumulation of deleterious lipid oxidation products and halting the spread of oxidative damage. In cancer cells, upregulated GSH synthesis and GPX4 activity contribute to an enhanced antioxidant defense, countering oxidative stress provoked by increased metabolic demands and exposure to therapeutic agents such as chemotherapy, radiotherapy, and immunotherapy. This ability of cancer cells to modulate their ferroptosis susceptibility through GSH metabolism underscores its potential as a therapeutic target. Additionally, GSH influences several key oncogenic and tumor-suppressive signaling pathways, including NFE2L2/NRF2, TP53/p53, NF-κB, Hippo, and mTOR, which collectively regulate responses to oxidative stress, affect metabolic processes, and modulate sensitivity to ferroptosis in cancer cells. This review explores recent advancements in understanding GSH's multifaceted role in ferroptosis, emphasizing its implications for cancer biology and therapeutic interventions.

The discovery of ferroptosis has brought a revolutionary breakthrough in heart failure treatment, and natural products, as a significant source of drug discovery, are gradually demonstrating their extraordinary potential in regulating ferroptosis and alleviating heart failure symptoms. In addition to chemically synthesized small molecule compounds, natural products have attracted attention as an important source for discovering compounds that target ferroptosis in treating heart failure.

Systematically summarize and analyze the research progress on improving heart failure through natural products' modulation of the ferroptosis pathway.

By comprehensively searching authoritative databases like PubMed, Web of Science, and China National Knowledge Infrastructure with keywords such as "heart failure", "cardiovascular disease", "heart disease", "ferroptosis", "natural products", "active compounds", "traditional Chinese medicine formulas", "traditional Chinese medicine", and "acupuncture", we aim to systematically review the mechanism of ferroptosis and its link with heart failure. We also want to explore natural small-molecule compounds, traditional Chinese medicine formulas, and acupuncture therapies that can inhibit ferroptosis to improve heart failure.

In this review, we not only trace the evolution of the concept of ferroptosis and clearly distinguish it from other forms of cell death but also establish a comprehensive theoretical framework encompassing core mechanisms such as iron overload and system xc-/GSH/GPX4 imbalance, along with multiple auxiliary pathways. On this basis, we innovatively link ferroptosis with various types of heart failure, covering classic heart failure types and extending our research to pre-heart failure conditions such as arrhythmia and aortic aneurysm, providing new insights for early intervention in heart failure. Importantly, this article systematically integrates multiple strategies of natural products for interfering with ferroptosis, ranging from monomeric compounds and bioactive components to crude extracts and further to traditional Chinese medicine formulae. In addition, non-pharmacological means such as acupuncture are also included.

This study fills the gap in the systematic description of the relationship between ferroptosis and heart failure and the therapeutic strategies of natural products, aiming to provide patients with more diverse treatment options and promote the development of the heart failure treatment field.

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

Kidney stones represent a highly prevalent urological disorder worldwide, with high incidence and recurrence rates. Calcium oxalate (CaOx) crystal-induced kidney injury serves as the foundational mechanism for the formation and progression of CaOx stones. Regulated cell death (RCD) such as ferroptosis, necroptosis, and pyroptosis are essential in the pathophysiological process of kidney injury. Ferroptosis, a newly discovered RCD, is characterized by its reliance on iron-mediated lipid peroxidation. Necroptosis, a widely studied programmed necrosis, initiates with a necrotic phenotype that resembles apoptosis in appearance. Pyroptosis, a type of RCD that involves the gasdermin protein, is accompanied by inflammation and immune response. In recent years, increasing amounts of evidence has demonstrated that ferroptosis, necroptosis, and pyroptosis are significant pathophysiological processes involved in CaOx crystal-induced kidney injury. Herein, we summed up the roles of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury. Furthermore, we delved into the curative potential of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury.

Ferroptosis is a form of necrotic cell death characterized by phospholipid oxidation. The cystine-glutamate antiporter (xCT), composed of solute carrier family 7 member 11 (SLC7A11) and SLC3A2, imports cystine for glutathione synthesis. Glutathione peroxidase 4 (GPX4) requires glutathione to counteract lipid peroxidation and prevent ferroptosis. Erastin, an xCT inhibitor, and Ras-selective lethal small molecule 3 (RSL3), a GPX4 inhibitor, suppress GPX4 function and induce ferroptosis. Tumor protein p53 (TP53) has a paradoxical role in ferroptosis regulation. Mouse double minute 2 homolog (MDM2), a negative regulator of TP53, is a key oncogene in well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS). Therefore, the present study explored the role of ferroptosis in DDLPS treatment response and resistance. Publicly available expression profiles of WDLPS, DDLPS and adipose tissue were analyzed, and the differential expression of ferroptosis-related genes regulated by the MDM2-TP53 pathway was identified in WDLPS and DDLPS. In vitro experiments were performed to assess the effects of erastin and RSL3 on the viability, lipid peroxidation and apoptosis of DDLPS cell lines. The results revealed that erastin and RSL3 induced lipid peroxidation and apoptosis, thereby exerting cytotoxic effects. In addition, nutlin-3, an MDM2 inhibitor, was demonstrated to increase lipid peroxidation and cytotoxicity when applied prior to erastin treatment. Notably, nutlin-3 also upregulated SLC3A2 expression in DDLPS cell lines, thereby enhancing cystine uptake. This increase in cystine uptake was suppressed by erastin. In addition, nutlin-3-induced SLC3A2 upregulation was abolished by TP53 knockdown. Nutlin-3 combined with erastin or RSL3 reduced absolute p-4EBP-1 levels in NDDLS-1 cells and p-p70S6 levels in both cell lines, with no significant impact on the p-4EBP-1/4EBP-1 and p-p70S6/p70S6 ratios. These results indicate that ferroptosis is a therapeutic vulnerability in the response to MDM2 inhibition in DDLPS. Furthermore, combining MDM2 inhibitors with ferroptosis-inducing agents may provide a potential therapeutic strategy for DDLPS and the role of mTOR in the pro-apoptotic effect of these combinations deserve further investigation.

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.

Atherosclerosis is the major pathological basis of cardiovascular diseases. Vascular smooth muscle cell (VSMC) dysfunction and death induced by oxidized low-density lipoprotein (oxLDL) play a key role in atherosclerosis. Ferroptosis is a novel iron-dependent lipid peroxidation regulated cell death, which is implicated in atherosclerosis. However, whether oxLDL induces VSMC ferroptosis and the specific mechanism is unclear.

To determine the effects of oxLDL on VSMC ferroptosis, LDH activity, MDA and Fe2+ content, glutathione peroxidase 4 (GPX4) expression and GPX enzyme activity were assayed. The level of lipid peroxidation was detected by C11 BODIPY fluorescence staining. RT-qPCR and Western blot were used to detect the mRNA and protein expressions of heat shock protein B1 (HSPB1), dipeptidyl peptidase 4 (DPP4) and nuclear factor kappa-B (NF-κB). The siRNAs, plasmids and Val-boropro were utilized to explore the roles of HSPB1/NF-κB/DPP4 in oxLDL-induced VSMC ferroptosis.

oxLDL increased LDH activity, Fe2+ content, lipid peroxidation and MDA content in VSMCs, which were inhibited by ferroptosis inhibitors Lip-1 and DFO. Moreover, oxLDL reduced GPX4 protein expression and GPX enzyme activity, indicating that oxLDL induces VSMC ferroptosis. Notably, HSPB1 inhibited oxLDL-induced VSMC ferroptosis by reducing the accumulation of Fe2+ and lipid peroxidation and increasing GPX4 expression and activity. In addition, HSPB1 suppressed oxLDL-induced VSMC ferroptosis by inhibiting DPP4 through NF-κB. Furthermore, Val-boropro could rescue oxLDL-induced ferroptosis in VSMCs with HSPB1 knockdown by inhibiting DPP4.

This study reveals for the first time that HSPB1 suppresses oxLDL-induced VSMC ferroptosis by inhibiting DPP4 through NF-κB, providing new strategies for the prevention and treatment of atherosclerosis.

Ferroptosis is a novel, iron-dependent form of non-apoptotic cell death characterized by the accumulation of lipid reactive oxygen species (ROS) and mitochondrial shrinkage. It is closely associated with the onset and progression of various diseases, especially cancer, at all stages, making it a key focus of research for developing therapeutic strategies. Numerous studies have explored the role of microRNAs (miRNAs) in regulating ferroptosis by modulating the expression of critical genes involved in iron metabolism and lipid peroxidation. Due to their diversity, unique properties, and dynamic expression patterns in diseases, exosomal miRNAs are emerging as promising biomarkers. Exosomes act as biological messengers, delivering miRNAs to target cells through specific internalization, thus influencing the ferroptosis response in recipient cells. This review summarizes the roles of miRNAs, with particular focus on exosomal miRNAs, in ferroptosis and their implications for cancer pathology. By examining the molecular mechanisms of miRNAs, we aim to provide valuable insights into potential therapeutic approaches.

Gliomas, which are complex primary malignant brain tumors known for their heterogeneous and invasive nature, present substantial challenges for both treatment and prognosis. Recent advancements in whole-genome studies have opened new avenues for investigating glioma mechanisms and therapies. Through single-cell analysis, we identified a specific cluster of cancer cell-related genes within gliomas. By leveraging diverse datasets and employing non-negative matrix factorization (NMF), we developed a glioma subtyping method grounded in this identified gene set. Our exploration delved into the clinical implications and underlying regulatory frameworks of the newly defined subtype classification, revealing its intimate ties to glioma malignancy and prognostic outcomes. Comparative assessments between the identified subtypes revealed differences in clinical features, immune modulation, and the tumor microenvironment (TME). Using tools such as the limma R package, weighted gene co-expression network analysis (WGCNA), machine learning methodologies, survival analyses, and protein-protein interaction (PPI) networks, we identified key driver genes influencing subtype differentiation while quantifying associated outcomes. This study not only sheds light on the biological mechanisms within gliomas but also paves the way for precise molecular targeted therapies within this intricate disease landscape.

This paper focuses on the mechanism underlying nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and subsequent hepatocyte ferroptosis. Iron is a pivotal trace element, but excessive iron deposition can lead to liver injury. Ferroptosis is a recognized, iron-dependent mode of programmed cell death that plays an important role in various liver diseases. NCOA4 is a key molecule mediating the selective autophagic degradation of ferritin. It affects ferroptosis by regulating intracellular free iron levels. NCOA4 expression is regulated by various factors, including cellular iron levels and oxidative stress. It was demonstrated that inhibition of NCOA4 can reduce iron-mediated cell death and mitigate liver damage, suggesting that NCOA4 may be a potential target for the prevention and treatment of liver diseases. Further in-depth studies of the molecular mechanism of NCOA4-mediated ferritinophagy and its relationship with iron-induced cell death can provide novel ideas for the diagnosis and treatment of liver diseases. The deficiency or abnormal expression of NCOA4 is closely associated with ferroptosis in a variety of liver diseases, including non-alcoholic fatty liver disease, alcoholic liver disease, drug-induced liver injury, and liver fibrosis. Future studies should focus on elucidating the dynamic changes in the NCOA4 regulatory network during specific pathological processes. This strategy can lay the foundation for drug development.

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.

Ferroptosis, an iron-dependent regulated cell death modality driven by lipid peroxidation cascades, has emerged as a critical pathogenic mechanism in tumorigenesis and therapeutic resistance. The long non-coding RNA HOTAIR (HOX transcript antisense RNA), previously recognized as a key epigenetic modulator in tumor biology, orchestrates malignant phenotypes through regulation of cell cycle dynamics, proliferative signaling, and metastatic potential. Despite these advances, the mechanistic interface between HOTAIR-mediated ceRNA networks and ferroptosis regulation in breast carcinogenesis remains undefined. Bioinformatic analysis and RT-qPCR validation precisely mapped the subcellular localization and interaction networks of this regulatory axis. Key findings revealed that HOTAIR silencing functionally promotes malignant phenotypes (proliferation, migration and invasion), and mechanistically serves as a molecular sponge for miR-206, thereby de-repressing CERS2 expression to modulate ferroptosis susceptibility. Given the established correlation between HOTAIR silencing and ferroptosis in BRCA, our data suggest that pharmacological induction of ferroptosis represents a promising therapeutic paradigm for this molecular subset. This work not only deciphers a novel HOTAIR/miR-206/CERS2 axis in ferroptosis regulation but also provides translational insights for developing biomarker-driven treatment strategies in refractory breast malignancies.

Ferroptosis is a novel iron-dependent type of programmed cell death that is characterized by the oxidation of lipids by divalent iron ions to produce lipid peroxides, which leads to cell death. Fucosyltransferase 11 (FUT11) is highly expressed in most tumors and is involved in tumorigenesis. However, there have been few studies regarding the relationship between FUT11 and ferroptosis. In this study, we found that FUT11 expression was abnormally high in gastric cancer (GC) cells and that the prognosis of patients with GC and high expression of FUT11 was poor. FUT11 expression was significantly correlated with the TNM stage of GC.Specific knockdown of FUT11 significantly inhibited the proliferation of GC cells, reduced the abundance of the key anti-ferroptotic protein glutathione peroxidase 4(GPX4), induced lipid peroxidation and ferroptosis in GC cells, and inhibited the proliferation of these cells. The overexpression of GPX4 reduced the inhibitory effect of FUT11 on GC cells. In addition, the knockdown of FUT11 significantly inhibited GC tumor growth in mice, and this inhibitory effect was reduced by the overexpression of GPX4. In conclusion, we have shown that FUT11 promotes GC progression by targeting GPX4, thereby inhibiting ferroptosis in GC cells. These findings suggest that FUT11 is a potential therapeutic target for GC.

Reactive oxygen species (ROS), regulators of cellular behaviors ranging from signaling to cell death, have complex production and control mechanisms to maintain a dynamic redox balance under physiological conditions. Redox imbalance is frequently observed in tumor cells, where ROS within tolerable limits promote oncogenic transformation, while excessive ROS induce a range of regulated cell death (RCD). As such, targeting ROS-mediated regulated cell death as a vulnerability in cancer. However, the precise regulatory networks governing ROS-mediated cancer cell death and their therapeutic applications remain inadequately characterized. In this Review, we first provide a comprehensive overview of the mechanisms underlying ROS production and control within cells, highlighting their dynamic balance. Next, we discuss the paradoxical nature of the redox system in tumor cells, where ROS can promote tumor growth or suppress it, depending on the context. We also systematically explored the role of ROS in tumor signaling pathways and revealed the complex ROS-mediated cross-linking networks in cancer cells. Following this, we focus on the intricate regulation of ROS in RCD and its current applications in cancer therapy. We further summarize the potential of ROS-induced RCD-based therapies, particularly those mediated by drugs targeting specific redox balance mechanisms. Finally, we address the measurement of ROS and oxidative damage in research, discussing existing challenges and future prospects of targeting ROS-mediated RCD in cancer therapy. We hope this review will offer promise for the clinical application of targeting oxidative stress-mediated regulated cell death in cancer therapy.

The ferroptosis of cardiomyocytes has been recognized as the core pathological mechanism of heart failure. During the evolution of cardiovascular diseases, the accumulation of angiotensin II and advanced glycation end products can lead to the excessive activation of the RAGE/TLR4-JNK1/2 pathway, which subsequently triggers ferritinophagy, clockophagy, and enhanced p53 activity, ultimately leading to cardiomyocyte ferroptosis. It is evident that deeply unraveling the specific mechanisms in this field and comprehensively evaluating potential drugs and therapeutic strategies targeting this pathway is crucial for improving the status of cardiomyocyte ferroptosis. However, our current understanding of this pathway's specific molecular biological mechanisms in the process of cardiomyocyte ferroptosis remains limited. In light of this, this paper first comprehensively reviews the historical context of ferroptosis research, compares the similarities and differences between ferroptosis and other standard modes of cell death, elucidates the core mechanisms of ferroptosis and its close connection with heart failure, aiming to establish a basic cognitive framework for readers on ferroptosis and its role in heart failure. Subsequently, the paper delves into the pivotal role of the RAGE/TLR4-JNK1/2 pathway in cardiomyocyte ferroptosis and its intricate molecular biological regulatory network. Furthermore, it systematically integrates various therapeutic approaches aimed at inhibiting RAGE, TLR4, and JNK1/2 activity to alleviate cardiomyocyte ferroptosis, encompassing RNA interference technology, gene knockout techniques, small molecule inhibitors, natural active ingredients, as well as traditional Chinese and Western medicines, with the ultimate goal of forging new avenues and strategies for the prevention and treatment of heart failure.

Subarachnoid hemorrhage (SAH) can cause severe neuronal damage and trigger multiple molecular mechanisms of cell death, among which ferroptosis has garnered significant attention due to its dependence on lipid peroxidation. In this study, ferroptosis-related markers were found to be significantly dysregulated in an in vitro SAH model, confirming the neuronal ferroptosis after SAH. Transcriptomic sequencing results indicated a marked downregulation of stearoyl-CoA desaturase 1 (SCD1), which was further validated by Western blot. Immunofluorescence demonstrated its colocalization with the neuronal marker NeuN. Overexpression of SCD1 effectively reduced ferroptosis-related markers and mitigated intracellular lipid accumulation. Additionally, supplementation with oleic acid (OA) which was the main product of SCD1, significantly alleviated hemoglobin (Hb)-induced ferroptosis. Furthermore, the ratio of saturated fatty acids (stearic acid, SA) to unsaturated fatty acids (OA) had a significant impact on neuronal survival. When the proportion of OA was increased (SA:OA = 1:2), ferroptosis was markedly inhibited. In conclusion, this study revealed the role and mechanism by which SCD1 affected neuronal ferroptosis by regulating oleic acid metabolism after SAH, providing a new potential target for mitigating neural injury after SAH.

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

Breast cancer (BC) is the most common malignant tumor and the leading cause of cancer-related deaths among women worldwide. Great progress has been recently achieved in controlling breast cancer; however, mortality from breast cancer remains a substantial challenge, and new treatment mechanisms are being actively sought. Programmed cell death (PCD) is associated with the progression and treatment of many types of human cancers. PCD can be divided into multiple pathways including autophagy, apoptosis, mitotic catastrophe, necroptosis, ferroptosis, pyroptosis, and anoikis. Ubiquitination is a post-translational modification process in which ubiquitin, a 76-amino acid protein, is coupled to the lysine residues of other proteins. Ubiquitination is involved in many physiological events and promotes cancer development and progression. This review elaborates the role of ubiquitin-specific protease (USP) in programmed cell death, which is common in breast cancer cells, and lays the foundation for tumor diagnosis and targeted therapy.

Oxidized low-density lipoprotein (oxLDL) activates the NF-κB signaling pathway through LOX-1, contributing to intervertebral disc degeneration (IVDD). Ferroptosis, a lipid peroxidation-driven cell death, is implicated in IVDD. This study investigates the role of ferroptosis in oxLDL-induced IVDD. Nucleus pulposus cells (NPCs) were treated with oxLDL, and ferroptosis and NF-κB p65 nuclear translocation were assessed. Bioinformatics analysis, silencing experiments, and inhibitors were used to validate the findings. In oxLDL-treated NPCs, LOX-1 and ferroptosis markers (MDA, Fe2+, lipid ROS) increased, while GSH decreased. These effects were mitigated by Liproxstatin-1 or shLOX-1. NF-κB p65 bound to LOX-1 and NOX1 promoters, forming a positive feedback loop. VAS2870 and Schisantherin A improved NPC viability and reduced ferroptosis. A mouse model showed worsening IVDD and ferroptosis over time. Clinical tissues revealed a strong correlation between LOX-1 and ferroptosis markers. oxLDL induces ferroptosis in NPCs via the LOX-1/NF-κB/NOX loop, advancing IVDD. Disrupting this loop in mice mitigated IVDD, highlighting the therapeutic potential of targeting this pathway.

Ferroptosis, a unique form of regulated cell death driven by iron accumulation and lipid peroxidation, has emerged as a critical process in various diseases. Recent evidence suggests its involvement in the pathogenesis of allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis. These conditions are characterized by chronic inflammation, oxidative stress, and immune dysregulation, all of which intersect with the molecular mechanisms of ferroptosis. Key regulators, such as glutathione peroxidase 4 (GPX4), the cystine/glutamate antiporter system Xc-, and iron metabolism pathways, play pivotal roles in ferroptotic processes and their contribution to allergic disease progression. This review explores the mechanistic link between ferroptosis and allergic diseases, emphasizing how oxidative damage and iron overload exacerbate inflammation and tissue injury. We also highlight emerging diagnostic biomarkers, including lipid peroxidation products and iron regulators, which could improve disease monitoring and stratification. Therapeutic strategies targeting ferroptosis, such as GPX4 activators, iron chelators, and lipid peroxidation inhibitors, show promise in preclinical\ studies, offering potential new avenues for treating allergic diseases. However, challenges remain in translating these findings into clinical applications. By integrating current knowledge, this review underscores the need for further research into ferroptosis as both a biomarker and therapeutic target in allergic diseases.

Examining how hypoglycemic medications affect brain function is one of the best approaches to addressing cognitive impairment. In this study, trelagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, was utilized to assess memory loss in diabetic rats through fear conditioning tests. Trelagliptin restored fear memory in diabetic rats that had been disrupted over a relatively long period (24 h) or extended period (5 days). Moreover, trelagliptin treatment reduced the higher incidence of neuronal cell death in the cerebral cortex, as observed via Nissl or hematoxylin and eosin staining. Subsequent analyses revealed that diabetic rats exhibited elevated levels of inflammatory cytokines (p-IKKα and p-NFκB) and a trend toward oxidative damage, indicated by malondialdehyde (MDA), superoxide dismutase 2 (SOD2), and glutathione peroxidase 4 (GPX4) detection. However, administration of trelagliptin reversed these markers to baseline levels. Additionally, trelagliptin activated p-AMPK, p-AKT, and p-GSK-3β. Notably, trelagliptin upregulated the expression of postsynaptic density protein 95 (PSD95) and synaptotagmin 1 (SYT1) while downregulating amyloid precursor protein (APP) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). These findings suggest that trelagliptin alleviates cognitive impairment in diabetic rats, likely through AMPK-AKT-GSK-3β-mediated mitigation of oxidative stress, enhancement of synaptic plasticity, and reduction of Aβ accumulation.

Ferroptosis is a type of regulated cell death caused by oxidative imbalance of the intracellular microenvironment. This causes the accumulation of toxic lipid peroxides, depicted by iron overload and lipid peroxidation, which results in disease development. The affected cell population displays unique morphological and biochemical features, which are distinct from other modes of cell death, like apoptosis, pyroptosis, and necroptosis. The individual pathways of each of these modes are interrelated and tend to counterbalance each other in the mechanism of cell death. The process of ferroptosis is associated with disturbances in iron metabolism, in conjunction with glutathione peroxidase and lipid peroxidation, culminating in a reduction of antioxidant capacity and accumulation of lipid peroxides in the dying cell. It has been observed that even excess cellular levels of iron can cause cell death, where ferroptosis is initiated by diminishing the levels of glutathione and glutathione peroxidase 4, and thus leading to excess build-up of lipid reactive oxygen species (ROS). In the case of a neoplastic cell, ferroptosis along with its regulators tends to orchestrate cell death and also affects cancer progression by modulation of proliferation activity, apoptosis suppression, metastasis, and drug resistance. Comprehending the complex network of molecular processes implicated in ferroptosis regulation is vital for developing targeted therapies for diseases where ferroptosis plays a significant role.

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

Ferroptosis, as novel type of regulated cell death that has garnered widespread attention over the past decade, has witnessed the continuous discovery of an increasing number of regulatory mechanisms. Trace metal elements play a multifaceted and crucial role in oncology. Interestingly, it has been increasingly evident that these elements, such as copper, are involved in the regulation of iron accumulation, lipid peroxidation and antiferroptotic systems, suggesting the existence of "nonferrous" mechanisms in ferroptosis. In this review, a comprehensive overview of the composition and mechanism of ferroptosis is provided. The interaction between copper metabolism (including cuproptosis) and ferroptosis in cancer, as well as the roles of other trace metal elements (such as zinc, manganese, cobalt, and molybdenum) in ferroptosis are specifically focused. Furthermore, the applications of nanomaterials based on these metals in cancer therapy are also reviewed and potential strategies for co-targeting ferroptosis and cuproptosis are explored. Nevertheless, in light of the intricate and ambiguous nature of these interactions, ongoing research is essential to further elucidate the "nonferrous" mechanisms of ferroptosis, thereby facilitating the development of novel therapeutic targets and approaches for cancer treatment.

Programmed cell death is a mechanism that is crucial for numerous physiological and pathological processes. Whereas p53-mediated apoptosis is a major cell death pathway in cancer, accumulating evidence indicates that p53 also has crucial roles in controlling different non-apoptotic cell death (NACD) pathways, including ferroptosis, necroptosis, pyroptosis, autophagy-dependent cell death, entotic cell death, parthanatos and paraptosis, and may regulate PANoptosis, cuproptosis and disulfidptosis. Notably, the function of p53 in these NACDs substantially contributes to its biological effects, particularly in cancer development and other pathological processes. In this Review, we discuss recent advances in understanding the roles and underlying mechanisms of p53-mediated NACDs, focusing on ferroptosis, necroptosis and pyroptosis. We discuss the complex and distinct physiological settings in which NACDs are regulated by p53, and potential targeting of p53-regulated NACDs for the treatment of cancer and other human diseases. Finally, we highlight several important questions concerning p53-regulated NACDs that warrant further investigation.

Inflammatory bowel disease (IBD) includes chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis, characterized by impaired function of the intestinal mucosal epithelial barrier. In recent years, ferroptosis, a novel form of cell death, has been confirmed to be involved in the pathological process of IBD and is related to various pathological changes, such as oxidative stress and inflammation. Recent studies have further revealed the complex interactions between the microbiome and ferroptosis, indicating that ferroptosis is an important target for the regulation of IBD by the gut microbiota and its metabolites. This article reviews the significant roles of gut microbial metabolites, such as short-chain fatty acids, tryptophan, and bile acids, in ferroptosis in IBD. These metabolites participate in the regulation of ferroptosis by influencing the intestinal microenvironment, modulating immune responses, and altering oxidative stress levels, thereby exerting an impact on the pathological development of IBD. Treatments based on the gut microbiota for IBD are gradually becoming a research hotspot. Finally, we discuss the potential of current therapeutic approaches, including antibiotics, probiotics, prebiotics, and fecal microbiota transplantation, in modulating the gut microbiota, affecting ferroptosis, and improving IBD symptoms. With a deeper understanding of the interaction mechanisms between the gut microbiota and ferroptosis, it is expected that more precise and effective treatment strategies for IBD will be developed in the future.

Trifluridine/Tipiracil (FTD/TPI, TAS102) has been approved for the treatment of patients with colorectal cancer (CRC) for its promising anticancer activity enabled by its incorporation into double strands during DNA synthesis. However, the mechanisms underlying the anticancer targets of FTD/TPI remain not fully understood. Here we report our observation of the activation of ferroptosis in CRC by FTD/TPI. Mechanistically, FTD/TPI directly promotes the ubiquitination and degradation of MDM2, thereby stabilizing the p53. Nuclear accumulation of p53 subsequently downregulates SLC7A11 expression, leading to ferroptosis. Furthermore, we observed that FTD/TPI combined with sulfasalazine (SAS), a system Xc- inhibitor, works in a synergistic manner to induce ferroptosis and further inhibit the proliferation of CRC cells. Finally, we confirmed the synergistic effect of SAS and FTD/TPI on patient-derived organoids in vitro and patient-derived xenograft mouse models in vivo. Our findings are the first to reveal that FTD/TPI induces ferroptosis via the p53-SLC7A11 axis and that SAS enhances the sensitivity and therapeutic effect of FTD/TPI. These findings suggest that the synergistic effect of FTD/TPI and SAS may represent a new therapeutic strategy for patients with CRC.

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.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high morbidity and mortality, as well as poor prognosis. Therefore, it is imperative to explore alternative therapeutic targets for HCC treatment. Ferroptosis and cuproptosis have recently been identified as metal-dependent cell death mechanisms that play significant roles in HCC treatment. This study identified potential cross-talk between ferroptosis and cuproptosis, including the common hub glutathione, common site of occurrence, mitochondria, shared epigenetic modification mode, RNA N6 methyladenosine modification, mutual inhibitor, nuclear factor erythroid 2-related factor 2, and dual regulator, p53. These findings provide a theoretical foundation for the joint induction of HCC cell death and effective inhibition of HCC progression. However, some immune cells are susceptible to ferroptosis or cuproptosis, which may impair or enhance anti-cancer immune function. We propose strategies to target specific targets molecules such as tripartite motif containing 25, ferroptosis suppressor protein 1, and peroxisome proliferator-activated receptor gamma or exploit the unique acidic environment surrounding cancer cells to precisely induce ferroptosis in cancer cells. This approach aims to advance the development of precision medicine for HCC treatment.

Ferroptosis is a unique form of cell death reliant on iron and lipid peroxidation. It disrupts redox balance, causing cell death by damaging the plasma membrane, with inducers acting through enzymatic pathways or transport systems. In cancer treatment, suppressing ferroptosis or circumventing it holds significant promise. Beyond cancer, ferroptosis affects aging, organs, metabolism, and nervous system. Understanding ferroptosis mechanisms holds promise for uncovering novel therapeutic strategies across a spectrum of diseases. However, detection and regulation of this regulated cell death are still mired with challenges. The dearth of cell, tissue, or organ-specific biomarkers muted the pharmacological use of ferroptosis. This review covers recent studies on ferroptosis, detailing its properties, key genes, metabolic pathways, and regulatory networks, emphasizing the interaction between cellular signaling and ferroptotic cell death. It also summarizes recent findings on ferroptosis inducers, inhibitors, and regulators, highlighting their potential therapeutic applications across diseases. The review addresses challenges in utilizing ferroptosis therapeutically and explores the use of machine learning to uncover complex patterns in ferroptosis-related data, aiding in the discovery of biomarkers, predictive models, and therapeutic targets. Finally, it discusses emerging research areas and the importance of continued investigation to harness the full therapeutic potential of targeting ferroptosis.

We present here a comprehensive update on recent advancements in the field of ferroptosis, with a particular emphasis on its metabolic underpinnings and physiological impacts. After briefly introducing landmark studies that have helped to shape the concept of ferroptosis as a distinct form of cell death, we critically evaluate the key metabolic determinants involved in its regulation. These include the metabolism of essential trace elements such as selenium and iron; amino acids such as cyst(e)ine, methionine, glutamine/glutamate, and tryptophan; and carbohydrates, covering glycolysis, the citric acid cycle, the electron transport chain, and the pentose phosphate pathway. We also delve into the mevalonate pathway and subsequent cholesterol biosynthesis, including intermediate metabolites like dimethylallyl pyrophosphate, squalene, coenzyme Q (CoQ), vitamin K, and 7-dehydrocholesterol, as well as fatty acid and phospholipid metabolism, including the biosynthesis and remodeling of ester and ether phospholipids and lipid peroxidation. Next, we highlight major ferroptosis surveillance systems, specifically the cyst(e)ine/glutathione/glutathione peroxidase 4 axis, the NAD(P)H/ferroptosis suppressor protein 1/CoQ/vitamin K system, and the guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin/dihydrofolate reductase axis. We also discuss other potential anti- and proferroptotic systems, including glutathione S-transferase P1, peroxiredoxin 6, dihydroorotate dehydrogenase, glycerol-3-phosphate dehydrogenase 2, vitamin K epoxide reductase complex subunit 1 like 1, nitric oxide, and acyl-CoA synthetase long-chain family member 4. Finally, we explore ferroptosis's physiological roles in aging, tumor suppression, and infection control, its pathological implications in tissue ischemia-reperfusion injury and neurodegeneration, and its potential therapeutic applications in cancer treatment. Existing drugs and compounds that may regulate ferroptosis in vivo are enumerated.

Flavonoids are a class of important polyphenolic compounds, renowned for their antioxidant properties. However, recent studies have uncovered an additional function of these natural flavonoids: their ability to inhibit ferroptosis. Ferroptosis is a key mechanism driving cell death in central nervous system (CNS) diseases, including both acute injuries and chronic neurodegenerative disorders, characterized by iron overload-induced lipid peroxidation and dysfunction of the antioxidant defense system. This review discusses the therapeutic potential of natural flavonoids from herbs and nutraceuticals as ferroptosis inhibitors in CNS diseases, focusing on their molecular mechanisms, summarizing findings from preclinical animal models, and providing insights for clinical translation. We specifically highlight natural flavonoids such as Baicalin, Baicalein, Chrysin, Vitexin, Galangin, Quercetin, Isoquercetin, Eriodictyol, Proanthocyanidin, (-)-epigallocatechin-3-gallate, Dihydromyricetin, Soybean Isoflavones, Calycosin, Icariside II, and Safflower Yellow, which have shown promising results in animal models of acute CNS injuries, including ischemic stroke, cerebral ischemia-reperfusion injury, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury. Among these, Baicalin and its precursor Baicalein stand out due to extensive research and favorable outcomes in acute injury models. Mechanistically, these flavonoids not only regulate the Nrf2/ARE pathway and activate GPX4/GSH-related antioxidant pathways but also modulate iron metabolism proteins, thereby alleviating iron overload and inhibiting ferroptosis. While flavonoids show promise as ferroptosis inhibitors for CNS diseases, especially in acute injury settings, further studies are needed to evaluate their efficacy, safety, pharmacokinetics, and blood-brain barrier penetration for clinical application.

Heart failure (HF) is a complex clinical syndrome influenced by diverse mechanisms of cellular demise. Recent findings indicate that ferroptosis also plays a role in the pathogenesis of HF. The present investigation utilized network pharmacology to investigate the suppressive impact of atorvastatin calcium (AC) on ferroptosis in a rat model of HF. The rats were categorized into three groups: the control group, the doxorubicin-induced group, and the doxorubicin (DOX)-induced group + AC-treated group. Echocardiography, enzyme-linked immunosorbent assay, and Western blotting were employed to evaluate cardiac structural and functional changes. Additionally, network pharmacology methods were utilized to ascertain the potential targets of AC and their interactions with regulatory genes associated with ferroptosis and HF. We identified four HF-related ferroptosis regulatory targets of AC: nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX1), tumor protein 53 (TP53), dipeptidyl peptidase 4 (DPP4), and glutathione peroxidase 4 (GPX4). Enrichment analysis revealed three signaling pathways influenced by AC in HF: ferroptosis, fluid shear stress and atherosclerosis, and lipid and atherosclerosis. This study indicated that AC can improve cardiac systolic dysfunction, reduce ventricular volume, and reverse myocardial remodeling in a doxorubicin-induced HF rat model. We highlight the role of ferroptosis in mediating this therapeutic effect through solute carrier family 7 member 11 (SLC7A11)/TP53 signaling pathway regulation and shed light on new directions for clinical treatment.

Protein quality control (PQC) plays a vital role in maintaining normal heart function, as cardiomyocytes are relatively sensitive to misfolded or damaged proteins, which tend to accumulate under pathological conditions. Ubiquitin-specific protease (USP) is the largest deubiquitinating enzyme family and a key component of the ubiquitin proteasome system (UPS), which is a non-lysosomal protein degradation machinery to mediate PQC in cells. USPs regulate the stability or activity of the target proteins that involve intracellular signaling, transcriptional control of inflammation, antioxidation, and cell growth. Recent studies demonstrate that the USPs can regulate fibrosis, lipid metabolism, glucose homeostasis, hypertrophic response, post-ischemic recovery and cell death such as apoptosis and ferroptosis in cardiomyocytes. Since myocardial cell loss is an important component of cardiomyopathy, therefore, these findings suggest that the UPSs play emerging roles in cardiomyopathy. This review briefly summarizes recent literature on the regulatory roles of USPs in the occurrence and development of cardiomyopathy, giving us new insights into the molecular mechanisms of USPs in different cardiomyopathy and potential preventive strategies for cardiomyopathy.

Background: Tumor cells engage in continuous self-replication by utilizing a large number of resources and capabilities, typically within an aberrant metabolic regulatory network to meet their own demands. This metabolic dysregulation leads to the formation of the tumor microenvironment (TME) in most solid tumors. Nanomedicines, due to their unique physicochemical properties, can achieve passive targeting in certain solid tumors through the enhanced permeability and retention (EPR) effect, or active targeting through deliberate design optimization, resulting in accumulation within the TME. The use of nanomedicines to target critical metabolic pathways in tumors holds significant promise. However, the design of nanomedicines requires the careful selection of relevant drugs and materials, taking into account multiple factors. The traditional trial-and-error process is relatively inefficient. Artificial intelligence (AI) can integrate big data to evaluate the accumulation and delivery efficiency of nanomedicines, thereby assisting in the design of nanodrugs. Methods: We have conducted a detailed review of key papers from databases, such as ScienceDirect, Scopus, Wiley, Web of Science, and PubMed, focusing on tumor metabolic reprogramming, the mechanisms of action of nanomedicines, the development of nanomedicines targeting tumor metabolism, and the application of AI in empowering nanomedicines. We have integrated the relevant content to present the current status of research on nanomedicines targeting tumor metabolism and potential future directions in this field. Results: Nanomedicines possess excellent TME targeting properties, which can be utilized to disrupt key metabolic pathways in tumor cells, including glycolysis, lipid metabolism, amino acid metabolism, and nucleotide metabolism. This disruption leads to the selective killing of tumor cells and disturbance of the TME. Extensive research has demonstrated that AI-driven methodologies have revolutionized nanomedicine development, while concurrently enabling the precise identification of critical molecular regulators involved in oncogenic metabolic reprogramming pathways, thereby catalyzing transformative innovations in targeted cancer therapeutics. Conclusions: The development of nanomedicines targeting tumor metabolic pathways holds great promise. Additionally, AI will accelerate the discovery of metabolism-related targets, empower the design and optimization of nanomedicines, and help minimize their toxicity, thereby providing a new paradigm for future nanomedicine development.

Parkinson's disease (PD) is a neurodegenerative disease, and emerging evidence has shown that iron deposition, ferroptosis and epigenetic modifications are implicated in the pathogenesis of PD. However, the interplay among these factors in PD has not been fully understood. In this review, we provide an overview of the current research progress on iron metabolism, ferroptosis and epigenetic alterations associated with PD. Furthermore, we present new frontiers concerning various epigenetic modifications related to iron metabolism and ferroptosis that might contribute to the pathology of PD. Notably, epigenetic modifications of iron metabolism and ferroptosis as both diagnostic and therapeutic targets in PD have been discussed. This opens new avenues for the regulation of iron homeostasis and ferroptosis in PD from epigenetic perspectives, and provides evidence for their potential implications in the diagnosis and treatment of PD.

Cancer remains one of the most formidable challenges in the medical field in this century, largely because of its poorly understood pathogenesis. Fortunately, recent advancements in the understanding of cancer pathogenesis have helped identify more therapeutic targets for improved treatment outcomes. The WNT signaling pathways are highly conserved cascades that participate in diverse physiologic processes, such as embryonic development, tissue homeostasis, and tissue regeneration. Ferroptosis, a unique iron-dependent form of cell death that is distinct from apoptosis, is driven by lipid peroxidation and excessive reactive oxygen species production. Emerging evidence shows that the dysregulation of WNT signaling pathways and ferroptosis, as well as their intricate cross-talk, plays crucial roles in cancer progression and therapeutic resistance, indicating their potential as targets for cancer therapies. This review provides a comprehensive overview of the current understanding of the cross-talk between WNT signaling pathways and ferroptosis in the pathogenesis and progression of cancer, with a specific focus on the regulatory role of the canonical WNT cascade in cancer-related ferroptosis. In addition, we discuss the pharmacologic mechanisms of current strategies that inhibit canonical WNT signaling and/or induce ferroptosis in cancer treatment. We propose that combining canonical WNT pathway inhibitors and ferroptosis inducers with current therapies represents a promising therapeutic strategy for personalized cancer treatment.

Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism, a common form of endocrine hypertension. Here, we demonstrate that Early Growth Response 1 (EGR1) plays a dual role in adrenal cell biology, regulating both oxidative stress and aldosterone production. Using RNA sequencing of RSL3-treated human adrenal cells and spatial transcriptomics of adrenal glands from patients with primary aldosteronism, we identify EGR1 as a key gene associated with RSL3-related oxidative stress and APAs. We show that EGR1 silencing decreases oxidative stress and increases CYP11B2 gene expression and aldosterone production in adrenal cells, while its overexpression has the opposite effects. Notably, EGR1 expression is downregulated in APAs and aldosterone-producing micronodules compared to the adjacent adrenal cortex, which correlates in part with decreased levels of oxidative stress markers. The adrenal cortex of pigs with secondary hyperaldosteronism shows decreased immunostaining of EGR1 and a marker of oxidative stress, suggesting a potential link between EGR1 expression, oxidative stress levels, and adrenocortical function. These findings reveal a novel mechanism linking EGR1 to oxidative stress regulation and aldosterone production in adrenal cells, with potential implications for the pathogenesis of APAs and other adrenocortical tumors.

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.

Anlotinib, an anti-angiogenic agent, has demonstrated significant anti-tumor effects in non-small cell lung cancer (NSCLC). However, whether anlotinib exerts its anti-tumor activity in NSCLC through ferroptosis, and its underlying mechanisms, remain unclear. This study revealed that anlotinib effectively inhibited the proliferation of NSCLC cells in a time- and dose-dependent manner. Treatment with anlotinib resulted in increased levels of ferroptosis targets (lipid reactive oxygen species and malondialdehyde) and p53 protein expression, while decreasing glutathione levels and the protein expression of solute carrier family 7 member 11 (xCT) and glutathione peroxidase 4 (GPX4). Notably, the ferroptosis inhibitor, Ferrostatin-1 (Fer-1), or the p53 inhibitor, Pifithrin-α (PFT-α), reversed the observed effects on ferroptosis induction in NSCLC cells. Consistently, our in vivo studies showed accelerated tumor growth rates for the anlotinib/Fer-1 group and the anlotinib/PFT-α group compared with administration of anlotinib alone. However, anlotinib-induced ferroptosis was suppressed in p53-deficient cells. Collectively, these findings confirm that anlotinib exerts potent anti-tumor effects both in vitro and in vivo by inducing ferroptosis by modulating the p53/xCT/GPX4 pathway specifically within NSCLC cells.

Iron overload is strongly associated with heart disease. Ferroptosis is a new form of regulated cell death indicated in cardiac ischemia-reperfusion (I/R) injury. However, the specific molecular mechanism of myocardial injury caused by iron overload in the heart is still unclear, and the involvement of ferroptosis in iron overload-induced myocardial injury is not fully understood. In this study, we observed that ferroptosis participated in developing of iron overload and I/R-induced cardiomyopathy. Mechanistically, we discovered that Parkin inhibited iron overload-induced ferroptosis in cardiomyocytes by promoting the ubiquitination of long-chain acyl-CoA synthetase 4 (ACSL4), a crucial protein involved in ferroptosis-related lipid metabolism pathways. Additionally, we identified p53 as a transcription factor that transcriptionally suppressed Parkin expression in iron-overloaded cardiomyocytes, thereby regulating iron overload-induced ferroptosis. In animal studies, cardiac-specific Parkin knockout mice (Myh6-CreER T2 /Parkin fl/fl ) fed a high-iron diet presented more severe myocardial damage, and the high iron levels exacerbated myocardial I/R injury. However, the ferroptosis inhibitor Fer-1 significantly suppressed iron overload-induced ferroptosis and myocardial I/R injury. Moreover, Parkin effectively protected against impaired mitochondrial function and prevented iron overload-induced mitochondrial lipid peroxidation. These findings unveil a novel regulatory pathway involving p53-Parkin-ACSL4 in heart disease by inhibiting of ferroptosis.