Cancer remains a significant barrier to human longevity and a leading cause of mortality worldwide. Despite advancements in cancer therapies, challenges such as cellular toxicity and drug resistance to chemotherapy persist. Regulated cell death (RCD), once regarded as a passive process, is now recognized as a programmed mechanism with distinct biochemical and morphological characteristics, thereby presenting new therapeutic opportunities. Ferroptosis, a novel form of RCD characterized by iron-dependent lipid peroxidation and unique mitochondrial damage, differs from apoptosis, autophagy, and necroptosis. It is driven by reactive oxygen species (ROS)-induced lipid peroxidation and is implicated in tumorigenesis, anti-tumor immunity, and resistance, particularly in tumors undergoing epithelial-mesenchymal transition. Moreover, ferroptosis is associated with ischemic organ damage, degenerative diseases, and aging, regulated by various cellular metabolic processes, including redox balance, iron metabolism, and amino acid, lipid, and glucose metabolism. This review focuses on the role of epigenetic factors in tumor ferroptosis, exploring their mechanisms and potential applications in cancer therapy. It synthesizes current knowledge to provide a comprehensive understanding of epigenetic regulation in tumor cell ferroptosis, offering insights for future research and clinical applications.

Targeting ferroptosis, cell death caused by the iron-dependent accumulation of lipid peroxides, and disruption of the redox balance are promising strategies in cancer therapy owing to the physiological characteristics of cancer cells. However, the detection of ferroptosis using in vivo imaging remains challenging. We previously reported that redox maps showing the reduction power per unit time of implanted tumor tissues via non-invasive redox imaging using a novel, compact, and portable electron paramagnetic resonance imaging (EPRI) device could be compared with tumor tissue sections. This study aimed to apply the EPRI technique to the in vivo detection of ferroptosis. Notably, redox maps reflecting changes in the redox status of tumors induced by the ferroptosis-inducing agent imidazole ketone erastin (IKE) were compared with the immunohistochemical images of 4-hydroxynonenal (4-HNE) in tumor tissue sections. Our comparison revealed a negative correlation between the reducing power of tumor tissue and the number of 4-HNE-positive cells. Furthermore, the control and IKE-treated groups exhibited significantly different distributions on the correlation map. Therefore, redox imaging using EPRI may contribute to the non-invasive detection of ferroptosis in vivo.

Regulated cell death is a form of cell death that is actively controlled by biomolecules. Several studies have shown that regulated cell death plays a key role after spinal cord injury. Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords. Autophagy, a complex form of cell death that is interconnected with various regulated cell death mechanisms, has garnered significant attention in the study of spinal cord injury. This injury triggers not only cell death but also cellular survival responses. Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis, ferroptosis, and autophagy. Therefore, this review aims to comprehensively examine the mechanisms underlying regulated cell deaths, the signaling pathways that modulate these mechanisms, and the potential therapeutic targets for spinal cord injury. Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury. Moreover, a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.

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

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.

Hepatocellular carcinoma (HCC) poses significant challenges due to its high malignancy and limited treatment options. FIN56 has emerged as a potent inducer of ferroptosis, yet its precise mechanism of action in HCC remains elusive.

Ferroptosis induction by FIN56 in HCC cells was assessed by quantifying malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), reactive oxygen species (ROS), glutathione (GSH) and Liperfluo levels, as well as evaluating changes in mitochondrial morphology.Additionally, cell proliferation and migration assays were performed to assess the functional impact of FIN56 on HCC cells. Tube formation and sprouting assays were performed using human umbilical vein endothelial cells (HUVECs). Proteomics analysis and immunosorbent assay (ELISA) identified angiogenin (ANG) as a secreted protein in the supernatant of HCC cells. Furthermore, both xenograft and syngeneic tumor models were established to investigate the potential impact of FIN56-induced ferroptosis on the tumor microenvironment.

RNA sequencing analysis of FIN56-treated HCC cells identified differentially expressed genes mainly associated with ferroptosis, cell proliferation, and migration. FIN56 effectively induced ferroptosis in HCC cells, while simultaneously inhibiting their proliferation and migration. RNA sequencing of HUVECs exposed to conditioned medium(CM) from FIN56-treated HCC cells (FIN56-CM) showed significant alterations in endothelial cell growth and gene expression. Further experiments revealed that FIN56-treated HCC cells secreted substantial levels of ANG after 12-18h, which activated the BMP6/ID1 signaling axis in endothelial cells, thereby enhancing their tube formation. Notably, the BMP signaling inhibitor LDN214117 partially suppressed ANG-mediated effects on endothelial cells. Finally, both ferroptosis and pro-angiogenic effects of FIN56 were confirmed in xenograft tumor model.

FIN56 induces ferroptosis in HCC cells, leading to the secretion of ANG. The secreted ANG acts as a critical signaling molecule, activating the BMP6/ID1 pathway in HUVECs and contributing to tumor microenvironment regulation.

The interplay between selenium (Se) metabolism and ferroptosis presents a compelling area of study in cancer biology. This review synthesizes the current understanding of key pathways implicated in ferroptosis susceptibility, with a focus on the role of selenoproteins, particularly glutathione peroxidase 4 (GPX4), which mitigates lipid peroxidation and prevents ferroptotic cell death through the system Xc-/GSH axis. Additionally, selenoprotein P contributes to Se transport, playing a crucial role in ferroptosis resistance observed in certain cancers. Targeting Se pathways, especially disrupting GPX4 and selenoprotein P functions, offers promising avenues for cancer therapy. The differential dependence of cancer cells on Se and selenoproteins highlights the potential for selective induction of ferroptosis in malignant cells. Future research should focus on unraveling the mechanistic underpinnings of Se-mediated ferroptosis and exploring combinatorial therapeutic strategies. This review sets the stage for innovative approaches that leverage Se metabolism to enhance cancer treatment efficacy through ferroptosis modulation. KEY MESSAGES: Selenium (Se) and selenoproteins regulate ferroptosis, a lipid peroxidation-driven form of cell death. GPX4, a Se-dependent enzyme, defends cells by neutralizing lipid hydroperoxides. Xc-/GSH/GPX4 and FSP1-CoQ10 pathways are critical in modulating ferroptosis susceptibility. Selenoprotein P, SEPHS2, and SQOR highlight vulnerabilities in Se-dependent cancer cell survival. Se's role in balancing antioxidant defense and ferroptosis offers therapeutic insights.

Approximately half of all cancers bear mutations in the tumor suppressor p53. Despite decades of research studying p53 function, treatment of p53-mutant cancers remains challenging owing to the effects of p53 mutations on many complex and interrelated signaling networks that promote tumor metastasis and chemoresistance. Mutations in p53 promote tumor survival by dysregulating cellular homeostasis and preventing activation of regulated cell death (RCD) pathways, which normally promote organismal health by eliminating dysregulated cells. Activation of RCD is a hallmark of effective cancer therapies, and p53-mutant cancers may be particularly susceptible to activation of certain RCD pathways. In this review, we discuss four RCD pathways that are the targets of emerging cancer therapeutics to treat p53-mutant cancers. These RCD pathways include E2F1-dependent apoptosis, necroptosis, mitochondrial permeability transition-driven necrosis, and ferroptosis. We discuss mechanisms of RCD activation, effects of p53 mutation on RCD activation, and current pharmaceutical strategies for RCD activation in p53-mutant cancers.

Ferroptosis is a unique mode of cell death driven by iron‑dependent phospholipid peroxidation, and its mechanism primarily involves disturbances in iron metabolism, imbalances in the lipid antioxidant system and accumulation of lipid peroxides. Protein processing, modification and folding in the endoplasmic reticulum (ER) are closely related regulatory processes that determine cell function, fate and survival. The uncontrolled proliferative capacity of malignant cells generates an unfavorable microenvironment characterized by high metabolic demand, hypoxia, nutrient deprivation and acidosis, which promotes the accumulation of misfolded or unfolded proteins in the ER, leading to ER stress (ERS). Ferroptosis and ERS share common pathways in several diseases, and the two interact to affect cell survival and death. Additionally, cell death pathways are not linear signaling cascades, and different pathways of cell death may be interrelated at multiple levels. Ferroptosis and ERS in ovarian cancer (OC) have attracted increasing research interest; however, both are discussed separately regarding OC. The present review aims to summarize the associations and potential links between ferroptosis and ERS, aiming to provide research references for the development of therapeutic approaches for the management of OC.

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.

In-situ tumor vaccination remains challenging due to difficulties in the exposure and presentation of tumor-associated neoantigens (TANs). In view of the central role of lipid metabolism in cell fate determination and tumor-immune cell communication, here we report a photo-controlled lipid metabolism nanoregulator (PLMN) to achieve robust in-situ adjuvant-free vaccination, which is constructed through hierarchically integrating photothermal-inducible arachidonate 15-lipoxygenase (ALOX15)-expressing plasmids, cypate and FIN56 into cationic liposomes. Near-infrared light (NIR) stimulation triggers on-demand ALOX15 editing and causes excessive accumulation of downstream pro-ferroptosis lipid metabolites. PLMN treatment enables efficient TAN release through ferroptosis-dependent membrane perturbation and facilitates their capture and processing by antigen-presenting cells via cationic lipid-mediated TAN enrichment. Meanwhile, upregulation of ALOX15-associated lipid metabolites also enhances M2-to-M1 phenotypic transition of tumor-associated macrophages through regulating tumor-macrophage metabolic crosstalk. PLMN treatment significantly enhance the robustness and durability of adaptive antitumor immunity in vivo, offering an approach for in-situ tumor vaccination in the clinic.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, progressive cartilage degradation, and bone erosion. Recent research has implicated ferroptosis not only in autoimmune hepatitis but also in the pathogenesis and progression of autoimmune disorders like RA. Consequently, numerous therapeutic strategies have begun to target the ferroptosis pathway, particularly in the design and development of nanodrug delivery systems (NDDSs). While previous reviews have comprehensively discussed the mechanisms of ferroptosis, related signaling pathways, and NDDS materials, recent studies have further elucidated the interplay between ferroptosis and various metabolic pathways, providing a robust theoretical basis for the design of NDDS-based ferroptosis strategies. This review focuses on investigating the role of ferroptosis in the development of RA, aiming to elucidate how targeting ferroptosis can offer novel therapeutic concepts and potential treatments for RA patients. Specifically, it summarizes the design strategies of ferroptosis-based NDDSs via different pathways and highlights the feasibility of RA treatment regimens based on the ferroptosis mechanism. Furthermore, the review critically discusses the current limitations of NDDSs and offers perspectives on future research directions in this field.

Inhibiting ferroptosis represents a promising strategy to combat ferroptosis-related diseases. Here we show that 428, a selenide-containing noscapine derivative, effectively inhibits ferroptosis in various cell lines by enhancing the stability and activity of GPX4. TRIM41 was identified as a novel E3 ubiquitin ligase of GPX4 and 428 was demonstrated to bind to the selenocysteine residue Sec46 of GPX4 via the formation of a transient and reversible Se-Se bond, thereby blocking the interaction between GPX4 and TRIM41, stabilizing GPX4 and enhancing its activity. This unique dynamic covalent binding mode was preliminarily validated by structure-activity relationship analysis and molecular docking studies. Importantly, we demonstrated that 428 treatment alleviates bleomycin-induced pulmonary fibrosis in vivo by inhibiting ferroptosis. Overall, our studies identified a novel stabilizer and activator of GPX4, offering a potential therapeutic approach for the treatment of ferroptosis-related diseases and uncovering a new mechanism for regulating GPX4 degradation.

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.

Ferroptosis, a newly discovered mode of cell death, is a type of iron-dependent regulated cell death characterized by intracellular excessive lipid peroxidation and imbalanced redox. As the liver is susceptible to oxidative damage and the abnormal iron accumulation is a major feature of most liver diseases, studies on ferroptosis in the field of liver diseases are of great interest. Studies show that targeting the key regulators of ferroptosis can effectively alleviate or even reverse the deterioration process of liver diseases. System Xc- and glutathione peroxidase 4 are the main defense regulators of ferroptosis, while acyl-CoA synthetase long chain family member 4 is a key enzyme causing peroxidation in ferroptosis. Generally speaking, ferroptosis should be suppressed in alcoholic liver disease, non-alcoholic fatty liver disease, and drug-induced liver injury, while it should be induced in liver fibrosis and hepatocellular carcinoma. In this review, we summarize the main regulators involved in ferroptosis and then the mechanisms of ferroptosis in different liver diseases. Treatment options of drugs targeting ferroptosis are further concluded. Determining different triggers of ferroptosis can clarify the mechanism of ferroptosis occurs at both physiological and pathological levels.

Small molecules that induce nonapoptotic cell death are of fundamental mechanistic interest and may be useful to treat certain cancers. Here we report that tegavivint, a drug candidate undergoing human clinical trials, can activate a unique mechanism of nonapoptotic cell death in sarcomas and other cancer cells. This lethal mechanism is distinct from ferroptosis, necroptosis and pyroptosis and requires the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase (TECR). TECR is canonically involved in the synthesis of very-long-chain fatty acids but appears to promote nonapoptotic cell death in response to CIL56 and tegavivint via the synthesis of the saturated long-chain fatty acid palmitate. These findings outline a lipid-dependent nonapoptotic cell death mechanism that can be induced by a drug candidate currently being tested in humans.

Aromatic amines (AAs) have been verified as a risk factor for bladder cancer (BCa). Most existing studies have focused on specific AAs types in BCa and assessed the impact of exposure to AAs on the prognosis of BCa patients; however, there is no comprehensive exploration of the mechanism of action. Therefore, this study explored the core hub genes (CHGs) involved in the interaction between major AAs and BCa through multi-database joint analysis to clarify the molecular mechanism of the AAS-induced occurrence and development of BCa and provide innovative insights in the diagnosis and treatment of AAS-induced BCa.

After the toxicity analysis of AAs, the toxicity regulatory network of AAs in BCa was constructed through network toxicology, and the targets that showed the causal relationship with BCa were screened by Mendelian randomization (MR) analysis. Comprehensive mechanism exploration, molecular docking and drug prediction analysis were conducted on CHGs defined by the protein-protein interaction (PPI) network.

The seven CHGs for the five AAs with different degrees of carcinogenicity to exert toxicity to BCa regulated the occurrence and development of BCa via multiple signaling pathways. Molecular docking confirmed the potential of the activation of these pathways caused by AAs. The results of drug prediction analysis suggested that rapamycin had a potential therapeutic prospect for AAs-induced BCa.

This study reveals the underlying molecular mechanism by which exposure to AAs leads to the occurrence and development of BCa, providing novel preventive and therapeutic insights for populations exposed to this exposure factor.

The disruption of ferroptosis, an emerging form of programmed cell death, is crucial in the development and aggressiveness of tumors. Meanwhile, the mechanisms and treatments that control ferroptosis in neuroblastoma (NB), a prevalent extracranial cancer in children, are still unknown. In this study, forkhead box C1 (FOXC1) and O-GlcNAc transferase (OGT) are identified as regulators of asparagine- and alanine-mediated ferroptosis repression in NB. Mechanistically, OGT facilitates FOXC1 stabilization via inducing O-GlcNAcylation in liquid condensates to increase the expression of asparagine synthetase (ASNS) and glutamate pyruvate transaminase 2 (GPT2), resulting in asparagine and alanine biogenesis, and subsequent synthesis of cystathionine β-synthase (CBS) or ferritin heavy chain 1 (FTH1). Meanwhile, exonic circular OGT RNA (ecircOGT) is able to encode a novel protein (OGT-570aa) containing domain essential for binding of OGT to FOXC1, which competitively decreases the OGT-FOXC1 interaction. Preclinically, miconazole nitrate facilitates the interaction of OGT-570aa with FOXC1, suppresses ferroptosis resistance of NB cells, and inhibits their growth, invasion, and metastasis. In clinical NB cases, higher OGT, FOXC1, ASNS, GPT2, CBS, or FTH1 levels are correlated with worse survival, while lower ecircOGT or OGT-570aa expression is associated with tumor progression. These results indicate that targeting the ecircOGT/OGT/FOXC1 axis inhibits asparagine- and alanine-mediated ferroptosis repression in NB progression.

Ferroptosis is implicated in cryodamage to sheep sperm, potentially due to glutathione peroxidase 4 (GPX4) degradation during freezing; however, the pathway underlying GPX4 degradation remains unclear. In this study, a comparison of cryoprotective effects between the autophagy inhibitor chloroquine (CQ) and the ubiquitination inhibitor MG132 revealed that 5 μM CQ treatment significantly enhanced the motility (p < 0.01) and sperm plasma membrane integrity rate (p < 0.01) of frozen-thawed sperm; no protective effects were observed in any MG132 treatment group. Mechanistic analysis indicated that CQ treatment substantially restored GPX4 protein expression (p < 0.01), and concurrently reduced lipid peroxidation (p < 0.01) and free iron ion accumulation (p < 0.01), in frozen-thawed sperm. These findings suggest that GPX4 degradation during cryopreservation occurs via the autophagy pathway. This study established a ferroptosis-GPX4-autophagy axis during sheep sperm cryopreservation and identified autophagy-mediated GPX4 loss as a potential target for enhancing sperm cryoprotection.

N-acetyl-l-cysteine (NAC) is a medication and a widely used antioxidant in cell death research. Despite its somewhat obscure mechanism of action, its role in inhibiting ferroptosis is gaining increasing recognition. In this study, we demonstrate that NAC treatment rapidly replenishes the intracellular cysteine pool, reinforcing its function as a prodrug for cysteine. Interestingly, its enantiomer, N-acetyl-d-cysteine (d-NAC), which cannot be converted into cysteine, also exhibits a strong anti-ferroptotic effect. We further clarify that NAC, d-NAC, and cysteine all act as direct reducing substrates for GPX4, counteracting lipid peroxidation. Consequently, only GPX4-rather than system xc-, glutathione biosynthesis, or ferroptosis suppressor protein 1-is necessary for NAC and d-NAC to prevent ferroptosis. Additionally, we identify a broad range of reducing substrates for GPX4 in vitro, including β-mercaptoethanol. These findings provide new insights into the mechanisms underlying the protective effects of NAC and other potential GPX4-reducing substrates against ferroptosis.

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.

Scale drop disease virus (SDDV) poses an escalating threat to global aquaculture, prompting an urgent need for research. Our study found that SDDV infection upregulates genes related to iron, oxidative stress, and lipid metabolism, causing iron overload, reactive oxygen species (ROS) accumulation, and ultimately ferroptosis. Among the tested antioxidants, vitamin C (VC) demonstrated the most potent inhibitory effect in mandarin fish, reducing SDDV-induced mortality by 37.5%. qPCR and IFA results showed that VC effectively suppressed SDDV infection; decreased ROS, lipid peroxidation (LPO), and iron levels; and enhanced glutathione peroxidase 4 (GPX4) expression in infected cells. Mechanistically, VC's inhibitory effect was reversed by the nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML-385, indicating an Nrf2-dependent pathway. VC promoted Nrf2 nuclear translocation and activated downstream antioxidant genes. Moreover, VC modulated inflammation by regulating pro- and anti-inflammatory factors. These findings suggest VC as a promising therapeutic for SDDV infection.

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.

Protein lipidation is a pivotal post-translational modification that increases protein hydrophobicity and influences their function, localization, and interaction network. Emerging evidence has shown significant roles of lipidation in the tumor microenvironment (TME). However, a comprehensive review of this topic is lacking. In this review, we present an integrated and in-depth literature review of protein lipidation in the context of the TME. Specifically, we focus on three major lipidation modifications: S-prenylation, S-palmitoylation, and N-myristoylation. We emphasize how these modifications affect oncogenic signaling pathways and the complex interplay between tumor cells and the surrounding stromal and immune cells. Furthermore, we explore the therapeutic potential of targeting lipidation mechanisms in cancer treatment and discuss prospects for developing novel anticancer strategies that disrupt lipidation-dependent signaling pathways. By bridging protein lipidation with the dynamics of the TME, our review provides novel insights into the complex relationship between them that drives tumor initiation and progression.

The outcome after liver transplantation has improved in recent years, which can be attributed to superior storage and transportation conditions of the organs, as well as better peri- and postoperative management and advancements in surgical techniques. Nevertheless, there is an increasing discrepancy between the need for organs and their availability. Consequently, the mortality rate on the waiting list is high and continues to rise. One way of counteracting this trend is to increase the use of "expanded criteria donors." This means that more and more donors will be included, especially those who are older and having additional comorbidities (eg, steatosis). A major complication of any transplantation is the occurrence of ischemia/reperfusion injury (IRI), which often leads to liver dysfunction and failure. However, there have been various promising approaches to minimize IRI in recent years, but an effective and clinically applicable method to achieve a better outcome for patients after liver transplantation is still missing. Thereby, the so-called marginal organs are predominantly affected by IRI; thus, it is crucial to develop suitable and effective treatment options for patients. Recently, regulated cell death mechanisms, particularly ferroptosis, have been implicated to play a major role in IRI, including the liver. Therefore, inhibiting this kind of cell death modality presents a promising therapeutic approach for the management of this yet untreatable condition. Thus, this review provides an overview of the role of ferroptosis in liver IRI and transplantation and discusses possible therapeutic solutions based on ferroptosis inhibition to restrain IRI in marginal organs (especially steatosis and donation after circulatory death organs).

Cancer cells display a distinctive defense mechanism against any exogenous moieties that renders all treatments inefficient. Glutathione, a thiol tripeptide plays a paradoxical role in cancer as intracellular glutathione (GSH) are voracious scavengers of free radicals produced by chemotherapy, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Cancer cells show Warburg effect, wherein the intracellular GSH levels are exceptionally enhanced to overcome the oxidative stress created by ROS/RNS production or by the other free radicals generated as side products of intracellular redox reactions. Therefore, redox resetting is essential to maintain the redox homeostasis for cell survival and their proliferation and trigger escalation of GSH levels. Nanotherapeutics have facilitated the targeted delivery of GSH-depleting agents in combination with radiotherapy, chemotherapy, and novel therapeutic interventions including chemodynamic therapy (CDT), photodynamic therapy (PDT), ferroptosis induction, sonodynamic therapy (SDT), and immunotherapy are being explored. This review aims to compile the strategic role of GSH in cancer cells, the importance of nanotherapeutics for GSH depletion in cancer to target numerous forms of programmed cell death (PCD), including apoptosis, ferroptosis, necroptosis, and autophagy.

Despite centuries of research, metastatic cancer remains incurable due to resistance to all conventional cancer therapeutics. Alternative strategies leveraging non-proliferative vulnerabilities in cancer are required to overcome cancer recurrence. Ferroptosis is an iron dependent cell death pathway that has shown promising pre-clinical activity in several contexts of therapeutic resistant cancer. However, ferroptosis sensitivity is highly variable across tissue types and cell states, posing a challenge for clinical translation. We describe a convergent phenotype induced by chemotherapy where cells surviving chemotherapy have dysregulated iron homeostasis, regardless of initial cell type or chemotherapy used. Elevated labile iron levels are counteracted by NRF2 signaling, yet the resulting antioxidant programs do not alleviate the labile iron burden. Selectively inhibiting GPX4 leads to uniform susceptibility to ferroptosis in surviving cells, highlighting the common reliance on lipid peroxidation defenses. Cellular iron dysregulation is a vulnerability of chemoresistant cancer cells that can be leveraged by triggering ferroptosis.

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.

Since its introduction in 2012, ferroptosis has garnered significant attention from researchers over the past decade. Unlike autophagy and apoptosis, ferroptosis is an atypical iron-dependent programmed cell death that falls under necrosis. It is regulated by various cellular metabolic and signaling processes, which encompass amino acid, lipid, iron, and mitochondrial metabolism. The initiation of ferroptosis occurs through iron-dependent phospholipid peroxidation. Notably, ferroptosis exhibits a dual effect and is associated with various diseases. A significant challenge lies in managing autoimmune disorders with unknown origins that stem from the reactivation of the immune system. Two contributing factors to autoimmunity are the aberrant stimulation of cell death and the inadequate clearance of dead cells, which can expose or release intracellular components that activate the immune response. Ferroptosis is distinct from other forms of cell death, such as apoptosis, necroptosis, autophagy, and pyroptosis, due to its unique morphological, biochemical, and genetic characteristics and specific relationship with cellular iron levels. Recent studies indicate that immune cells can both induce and undergo ferroptosis. To better understand how ferroptosis influences immune responses and its imbalance in disease, a molecular understanding of the relationship between ferroptosis and immunity is essential. Consequently, further research is needed to develop immunotherapeutics that target ferroptosis. This review primarily focuses on the role of ferroptosis in immune-related disorders.

Previous experiments have revealed that curcumin exerts potential antitumor effect by inducing apoptosis and ferroptosis of tumor cells. However, its low solubility and bioavailability, as well as fast metabolism limit its clinical use. The structural modification of curcumin is beneficial for the discovery of potential candidate drugs for cancer treatment. Here, three new series of curcumin derivatives including 25 compounds were synthesized at active sites on benzene ring and β-diketone moiety. Further antiproliferative activities against five cancer cell lines (Hela, A549, HepG2, MCF-7 and HT-29) in vitro showed that compound 4a-4e displayed remarkable anti-tumor effect against A549, HepG2, MCF-7 and HT-29. Of them, compound 4d is particularly prominent against MCF-7, with IC50 of 1.39 μM. Preliminary mechanism found that compound 4d could trigger ferrous ions and ROS accumulation, increase MDA level in MCF-7 cells, while significantly down-regulate GPX4 level in dose-dependent manner. Western Blot results discovered that compound 4d decreased the ratio of SLC7A11 to GAPDH and GPX4 to β-actin. Docking results indicated that compound 4d had good binding affinity to the active site of GPX4 (PDB ID: 7u4n and 7u4k). In conclusion, compound 4d may be potential anti-tumor agent, which induces ferroptosis in MCF-7 cells through activating SLC7A11/GPX4 axis.

Ferroptosis is a regulated cell death characterized by excessive accumulation of toxic lipid reactive oxygen species (ROS). Ferroptosis is an underlying cause in some human diseases, including the drug-induced liver injury. The present study aims to determine whether 4-hydroxyestrone (4-OH-E1) and 4-hydroxyestradiol (4-OH-E2), two endogenous catechol estrogens, can prevent chemically-induced ferroptotic hepatocyte injury in vitro and in vivo. The induction of ferroptotic cell death by erastin and RSL3 in rat H-4-II-E and human HuH-7 hepatoma cells is used as in vitro models. 4-OH-E1 and 4-OH-E2 each exhibit a strong protection against erastin/RSL3-induced ferroptosis in H-4-II-E hepatoma cells, and they also strongly abrogate erastin/RSL3-induced accumulation of cellular NO, ROS and lipid-ROS. A similar protective effect is observed with 4-OH-E1 and 4-OH-E2 in RSL3-induced ferroptosis in HuH-7 cells. Mechanistically, these two catechol estrogens protect hepatoma cells against chemically-induced ferroptosis mainly through binding to cellular PDI protein with a high affinity, which leads to inhibition of PDI-catalyzed NOS dimerization (activation), thereby preventing the accumulation of cellular NO, ROS and lipid-ROS. In addition, the direct antioxidant activity of these two estrogens may also partially contribute to their cytoprotective effect. In vivo animal studies show that 4-OH-E1 and 4-OH-E2 also have a strong protective effect against acetaminophen-induced liver injury in a mouse model. Together, the results of this study demonstrate that 4-OH-E1 and 4-OH-E2 are endogenous factors with a strong protective activity against chemically-induced hepatocyte injury both in vitro and in vivo.

TAp73, a transcriptionally active isoform of the p73 gene, is essential for epithelial tissue development. Ferroptosis, a regulated form of cell death characterized by lipid peroxidation and reactive oxygen species (ROS) accumulation, has been increasingly studied in recent years. However, its role in epithelial cells and the regulatory function of TAp73 in this context remain poorly understood.

We investigated the role of TAp73 in epithelial cell proliferation and ferroptosis using ectopic overexpression and RNA interference approaches. Cell proliferation was assessed through colony formation and DNA synthesis assays. Ferroptosis was induced using RSL3, and the effects were evaluated by measuring cell viability, ROS levels, and the expression of ferroptosis-associated genes PTGS2 and TFRC.

TAp73 overexpression significantly increased p21 expression, suppressed colony formation and DNA synthesis, thereby inhibiting cell proliferation. In contrast, TAp73 knockdown reduced p21 levels and enhanced cell proliferation. RSL3 treatment induced a dose-dependent increase in cell death and ROS accumulation, confirming the susceptibility of epithelial cells to ferroptosis. Furthermore, TAp73 overexpression enhanced RSL3-induced ferroptosis by upregulating PTGS2 and TFRC, while TAp73 knockdown diminished their expression, reducing oxidative stress and lipid peroxidation.

TAp73 acts as a dual regulator of epithelial cell fate by inhibiting proliferation and promoting ferroptosis. These findings reveal a novel role for TAp73 in epithelial cell biology and suggest potential therapeutic targets for diseases involving epithelial cell death.

Spinal cord injury (SCI) is a severe traumatic condition that frequently results in various neurological disabilities, including significant sensory, motor, and autonomic dysfunctions. Ferroptosis, a recently identified non-apoptotic form of cell death, is characterized by the accumulation of reactive oxygen species (ROS), intracellular iron overload, and lipid peroxidation, ultimately culminating in cell death. Recent studies have demonstrated that ferroptosis plays a critical role in the pathophysiology of SCI, contributing significantly to neural cell demise. Three key cellular enzymatic antioxidants such as glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and dihydroorotate dehydrogenase (DHODH), have been elucidated as crucial components in the defense against ferroptosis. Natural products, which are bioactive compounds mostly derived from plants, have garnered considerable attention for their potential therapeutic effects. Numerous studies have reported that several natural products can effectively mitigate neural cell death and alleviate SCI symptoms. This review summarizes fifteen natural products containing (-)-Epigallocatechin-3-gallate (EGCG), Proanthocyanidin, Carnosic acid, Astragaloside IV, Trehalose, 8-gingerol, Quercetin, Resveratrol, Albiflorin, Alpha-tocopherol, Celastrol, Hispolon, Dendrobium Nobile Polysaccharide, Silibinin, and Tetramethylpyrazine that have shown promise in treating SCI by inhibiting ferroptosis. Additionally, this review provides an overview of the mechanisms involved in these studies and proposes several perspectives to guide future research directions.

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.

Diabetic kidney disease (DKD) is a major diabetic microvascular complication that still lacks effective therapeutic drugs. Ferroptosis is a recently identified form of programmed cell death that is triggered by iron overload. It is characterized by unrestricted lipid peroxidation and subsequent membrane damage and is found in various diseases. Accumulating evidence has highlighted the crucial roles of iron overload and ferroptosis in DKD. Here, we review iron metabolism and the biology of ferroptosis. The role of aberrant ferroptosis in inducing diverse renal intrinsic cell death, oxidative stress, and renal fibrosis in DKD is summarized, and we elaborate on critical regulatory factors related to ferroptosis in DKD. Finally, we focused on the significance of ferroptosis in the treatment of DKD and highlight recent data regarding the novel activities of some drugs as ferroptosis inhibitors in DKD, aiming to provide new research targets and treatment strategies on DKD.

Ferroptosis has been characterised by disruption of the cell membrane through iron-related lipid peroxidation. However, regulation of iron homeostasis in lung cancer cells that are resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains unclear. Transcriptome analysis identified a significant downregulation of apoptosis-associated tyrosine kinase (AATK) mRNA expression in gefitinib-resistant PC9 (PC9-GR) cells, which were found to be more susceptible to ferroptosis inducers. An in-depth analysis of publicly available datasets revealed that downregulation of AATK mRNA was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma. Knockdown of AATK-sensitised PC9, HCC827, and H441 cells to the ferroptosis inducer RSL3, whereas ectopic expression of AATK reduced RSL3-induced cell death in PC9-GR and HCC827-GR cells. Compared to PC9 cells, PC9-GR cells exhibited higher transferrin uptake, endosome recycling rate, and increased intracellular iron levels. Blocking iron transport reduced RSL3-induced ferroptosis in PC9-GR cells. Mechanistic studies showed that AATK localised to both early and recycling endosomes. Knockdown of AATK facilitated endosome recycling and elevated intracellular ferrous iron (Fe2+) levels in PC9 cells. Conversely, ectopic expression of AATK delayed endosome recycling and reduced intracellular Fe2+ levels in PC9-GR cells. Inhibition of AATK downregulation-induced iron accumulation decreased RSL3-induced ferroptosis. Taken together, our study indicates that the downregulation of AATK contributes to endosome recycling and iron accumulation, leading to an increased susceptibility to ferroptosis in EGFR-TKI-resistant lung cancer cells. © 2025 The Pathological Society of Great Britain and Ireland.

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.

Radioresistance is a major clinical challenge and the underlying mechanism has not been thoroughly elucidated. In this study, a radioresistant (RR) cell line is established to explore the transcriptomic signatures of radioresistance in colorectal cancer (CRC). KEGG enriched pathway analysis demonstrated that ferroptosis is inactivated in RR cells. Further detection confirmed that radiotherapy can promote ferroptosis, and ferroptosis inactivation is one of the hallmarks of radioresistance in CRC. What's more, induction of ferroptosis can restore the radiosensitivity of CRC cells. Then, we performed RNA sequencing to compare gene expression between parental and RR cells, and cells pretreated with or without RSL3. Via high-throughput screening, NUPR1 was identified as a potential candidate for ferroptosis-mediated radioresistance in CRC. CRC cells can acquire radiation resistance by NUPR1-mediated ferroptosis suppression in the NUPR1-overexpressing cell line. More importantly, ZZW-115, an NUPR1 inhibitor, can sensitise RR cells to radiotherapy. Overall, our findings identify ferroptosis inactivation linked with resistance to radiotherapy. Besides, NUPR1 can promote radiation resistance by inhibiting ferroptosis, and targeting NUPR1 may be a potential strategy to relieve radioresistance associated with ferroptosis in CRC.