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.

Metallic cardiovascular stents are crucial for preventing atherosclerosis-induced infarction by offering mechanical support. However, the effects of metal ions released from these stents on atherosclerosis remain ambiguous. This study evaluates the potential impact posed by the degradation products of magnesium-based stents, with a focus on ferroptosis, a key mechanism driving atherosclerosis. Remarkably, our results demonstrate that Mg effectively inhibits ferroptosis in human umbilical vein endothelial cells and in murine, rat and rabbit models. Our studies reveal that magnesium ions impede the dephosphorylation of ERK proteins, thereby enhancing the expression of SLC7A11 and GCL proteins via activation of the MAPK pathway mechanistically. Additionally, magnesium ions downregulate ACSL4 protein expression, leading to decreased levels of acyl-CoA and ether-phospholipids. Eventually, multiple animal experiments indicate that biodegradable Mg stents can inhibit ferroptosis and decelerate the progression of arteriosclerosis, highlighting the therapeutic potential of Mg stents in treating arteriosclerosis.

Eleven previously undescribed lindenane sesquiterpenoids, lindaggrols A-K (1-11), were isolated from the roots of Lindera aggregata (Sims) Kosterm, together with five known ones. Their structures were elucidated by HR-ESI-MS, NMR, and single-crystal X-ray diffraction analyses. Lindaggrol A (1) is an undescribed rearranged dinor-lindenane with an unprecedented 3/5/5 tricyclic scaffold. All isolated compounds were assayed for their neuroprotective effects against erastin-induced ferroptosis in HT-22 cells. Among them, 3, 12 and 14 exhibited significant neuroprotective activities with EC50 values ranging from 1.4 to 8.7 μM.

Berberine, a key bioactive component of Coptis rhizome, has been extensively studied for its therapeutic effects on various diseases. This research aimed to investigate the potential benefits of berberine in treating tendinopathy and to elucidate the underlying mechanisms through animal and laboratory studies. Our findings indicated that berberine effectively treated type I collagenase-induced tendinopathy in rats, confirmed by cellular-level validation. At the molecular level, berberine reduced the activation of the cGAS-STING signaling pathway and decreased the accumulation of malondialdehyde (MDA) and reactive oxygen species (ROS) in both animal models and cell cultures. Additionally, berberine upregulated the expression of glutathione (GSH) and glutathione peroxidase 4 (GPX4) in tissues. These results suggested that berberine alleviated ferroptosis via the cGAS-STING pathway, thus exerting therapeutic effects on tendinopathy. To validate these findings further, we administered the ferroptosis inducer Imidazole Ketone Erastin (IKE) to evaluate the effects of berberine. IKE significantly diminished the therapeutic effects of berberine on tendinopathy, as indicated by the previously mentioned markers. Thus, berberine mitigated ferroptosis by inhibiting the cGAS-STING pathway, highlighting its potential in managing tendinopathy.

Cancer remains a significant threat to human health due to its multifaceted causes and complex pathogenesis. While advancements in research have improved outcomes for many cancer patients, treatments for specific tumor types still face limitations. Dihydroartemisinin (DHA), an active metabolite of artemisinin and its derivatives, has proven to be an effective anti-malarial agent. Recently, its anticancer potential has garnered increasing interest as it acts through multiple molecular pathways, including anti-proliferation, induction of apoptosis, autophagy and endoplasmic reticulum (ER) stress, anti-metastasis, inhibition of angiogenesis, and modulation of immune function. This review aims to thoroughly explain and summarize the mechanisms of DHA against cancer and the latest progress in this field. Due to the insufficiency of monotherapy in effectively treating cancer, the use of chemotherapy in combination with alternative therapies has witnessed a notable increase in popularity. DHA has shown synergistic anti-tumor efficacy with a range of therapeutic drugs, but its co-delivery with chemotherapeutics has been limited by low solubility and bioavailability. Nanotechnology-assisted co-delivery of anti-tumor agents, utilizing advanced stimulus-triggered drug release systems in tumor cells, offers the potential to enhance selective delivery and increase antitumor efficacy. Additionally, this article provides suggestions for further research on the anticancer effects of DHA.

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

Ferroptosis is a form of regulated cell death resulting from excessive lipid peroxidation. Sulfasalazine (SAS), an anti-inflammatory drug, can induce ferroptosis through inhibiting the system Xc- and triggering glutathione depletion. SAS has attracted considerable interest in recent years because of its potential for repurposing as an anticancer agent. Our recent studies have shown that protein disulfide isomerase (PDI) is an upstream mediator of chemically-induced ferroptosis through catalyzing the dimerization of nitric oxide synthase (NOS) and NO accumulation in cultured HT22 hippocampal neuronal cells. The present study aims to investigate SAS-induced ferroptotic cell death in HT22 cells with a focus on determining the role of PDI in mediating SAS-induced ferroptosis. We find that SAS induces ferroptotic cell death in HT22 cells, which is accompanied by a time-dependent sequential increase in the accumulation of cellular NO, ROS and lipid-ROS. We find that treatment of HT22 cells with SAS activates PDI-mediated iNOS activation (dimerization) and NO accumulation. In addition, SAS also strongly upregulates iNOS protein levels in HT22 cells. PDI knockdown or pharmacological inhibition of PDI's activity each suppresses SAS-induced iNOS dimerization, which is associated with abrogation of SAS-induced accumulation of NO, ROS and lipid-ROS, and a strong protection against ferroptotic cell death. On the other hand, PDI activation through the use of a TrxR1 inhibitor can strongly sensitize cells to SAS-induced ferroptosis. Together, these experimental observations demonstrate a crucial role of PDI in SAS-induced ferroptosis in a cell culture model through the activation of the PDI → NOS → NO → ROS/lipid-ROS pathway. Insights gained from this study also provide effective strategies to selectively sensitizing human cancer cells to SAS-induced ferroptosis, such as through the use of NO-releasing agents or TrxR1 inhibitors.

Coral reef ecosystems are facing severe deterioration due to escalating global temperatures and human-induced activities. Combined nitrate and heat stress can exacerbate coral bleaching, however, the underlying mechanism is still unclear. In the present study, we assessed the bleaching status of Acropora hyacinthus, a reef-building coral species, under high temperature and nitrate stress conditions using chemostat cultivation. We observed nitrate enrichment (9 μM) induced a significant reduction in photosystem efficiency (Fv/Fm) of Symbiodiniaceae and an increased thermal bleaching of corals under high temperature (30 °C). Nitrate exposure promoted the proliferation of Enterobacteriaceae and Vibrionaceae, which are bacterial families, potentially augmenting the coral's susceptibility to disease while exerting negligible effects on the fungal community. Alterations were observed in the metabolic pathways of both the coral hosts and Symbiodiniaceae, including down-regulated folate biosynthesis and inflammatory mediator regulation of TRP channels. Our findings indicate that nitrate enrichment under heat stress disrupts the metabolism of coral holobionts through altering bacterial communities, ultimately leading to increased coral bleaching.

Scale drop disease virus (SDDV) is a distinct member in genus Megalocytivirus of family Iridoviridae, garnering increasing attention due to its significant threat to teleost. Ferroptosis is a new type of cell death discovered recently and involved in various viral infections. Knowledges on SDDV induced ferroptosis remains unclear. Here, we demonstrated that SDDV infection triggers ferroptosis, as evidenced by hallmark features such as iron overload, massive lipid peroxides accumulation, glutathione depletion and glutathione peroxidase 4 (gpx4) downregulation. SDDV-infected MFF-1 cells exhibited increased reactive oxygen species production and mitochondrial shrinkage. Treatment with Ferrostatin-1, a potent ferroptosis inhibitor, significantly attenuated SDDV replication in MFF-1 cells and could improve the survival of mandarin fish upon SDDV challenge. Treatment with an iron chelator mitigated ferroptosis and reduced the mortality of mandarin fish following SDDV infection, suggesting that SDDV-induced ferroptosis is iron-dependent. Finally, we demonstrated that SDDV infection could upregulate the expression of transferrin receptor protein 1 (TfR1), a critical iron transporter, to disrupt cellular iron homeostasis, induce ferroptosis, and then facilitate viral infection. Collectively, our findings provide compelling evidence that SDDV infection induces ferroptosis by targeting TfR1 to facilitate virus infection. Inhibiting ferroptosis maybe represent a promising anti-viral strategy for combating SDDV infection in aquaculture.

Plant cell death is mediated by calcium, iron, and reactive oxygen species (ROS) signaling in plant immunity. The reconstruction of a nucleotide-binding leucine-rich-repeat receptor (NLR) supramolecular structure, called the resistosome, is intimately involved in the hypersensitive response (HR), a type of cell death involved in effector-triggered immunity (ETI). Iron is a crucial redox catalyst in various cellular reactions. Ferroptosis is a regulated, non-apoptotic form of iron- and ROS-dependent cell death in plants. Pathogen infections trigger iron accumulation and ROS bursts in plant cells, leading to lipid peroxidation via the Fenton reaction and subsequent ferroptosis in plant cells similar to that in mammalian cells. The small-molecule inducer erastin triggers iron-dependent lipid ROS accumulation and glutathione depletion, leading to HR cell death in plant immunity. Calcium (Ca2+) is another major mediator of plant immunity. Cytoplasmic Ca2+ influx through calcium-permeable channels, the resistosomes, mediates iron- and ROS-dependent ferroptotic cell death under reduced glutathione reductase (GR) expression levels in the ETI response. Acibenzolar-S-methyl (ASM), a plant defense activator, enhances Ca2+ influx, ROS and iron accumulation, and lipid peroxidation to trigger ferroptotic cell death. These breakthroughs suggest a potential role for Ca2+ signaling in ferroptosis and its coordination with iron and ROS signaling in plant immunity. In this review, we highlight the essential roles of calcium, iron, and ROS signaling in ferroptosis during plant immunity and discuss advances in the understanding of how Ca2+-mediated ferroptotic cell death orchestrates effective plant immune responses against invading pathogens.

Intestinal ischemia-reperfusion (II/R) injury represents a life-threatening and complex pathophysiological process that remains challenging to treat clinically, and emerging evidence suggests that ferroptosis plays an essential role in its pathogenesis. This study aimed to investigate whether extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) can mitigate II/R-induced ferroptosis in a murine model. Using a bioinformatics database, we initially identified genes with abnormal expression patterns in II/R injury. Then, we confirmed the association between II/R injury, ferroptosis, and the HMGB1/SREBF2 axis through in vivo and in vitro experiments. To determine the role of HMGB1 in hypoxia/reoxygenation (H/R)-induced ferroptosis in Caco-2 cells, we transfected cells with either sh-HMGB1 or control sh-NC constructs and developed an H/R model in vitro. Subsequently, we examined factors regulating HMGB1-mediated ferroptosis in Caco-2 cells and assessed the effect of BMSC-EVs on this process. To further explore the mechanism underlying the protective effects of BMSC-EVs in II/R injury, we screened for miRNAs with reduced expression during II/R and verified their involvement. Among these, miR-378a-3p was identified as a candidate for regulating ferroptosis. To confirm its functional role, we treated II/R mice with BMSC-EVs overexpressing miR-378a-3p and assessed the outcomes. Our findings revealed that HMGB1, which is a key regulatory factor of ferroptosis, was significantly upregulated during II/R injury, and its knockdown alleviated H/R-induced ferroptosis in Caco-2 cells. We also found that SREBF2 directly regulates HMGB1 expression to promote H/R-induced ferroptosis in vitro. Importantly, BMSC-EVs alleviated II/R injury by suppressing ferroptosis in Caco-2 cells, and mechanistically, miR-378a-3p, a miRNA derived from BMSC-EVs, inhibited II/R-induced ferroptosis by modulating the SREBF2/HMGB1 axis. In conclusion, BMSC-EVs may exert protective effects against II/R injury by delivering miR-378a-3p, which regulates the SREBF2/HMGB1 axis to suppress ferroptosis, providing important insights into the pathological mechanisms underlying II/R injury and potential therapeutic strategies for its management.

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.

Benzene, a common environmental contaminant that significantly impacts the hematopoietic system. Although benzene toxicity has been well documented, the exact molecular mechanisms involved remain unclear. This study aimed to explore the role of ferroptosis in benzene-induced hematotoxicity and uncover the underlying mechanisms. Rats exposed to benzene exhibited reduced peripheral blood cell counts, elevated serum iron concentrations, and increased expression of proteins associated with autophagy and ferroptosis within their bone marrow (BM) cells. In addition, inhibition of autophagy in benzene-exposed rats alleviated weight loss, peripheral blood cell abnormalities, iron dysregulation, and ferroptosis signaling activation. To further investigate the cellular mechanisms, we conducted in vitro experiments in which the benzene metabolite hydroquinone (HQ) was found to elicit ferroptosis and disrupt autophagy functionality in JHP cells. Meanwhile, the autophagy inhibitor 3-methyladenine (3-MA) alleviated these adverse effects. Additionally, HQ induced damage to mitochondria in JHP cells, as evidenced by a decline in mitochondrial membrane potential (MMP) and an increase in mitochondrial reactive oxygen species (mtROS). Collectively, our results demonstrate that mtROS-dependent autophagy participates in ferroptosis induced by benzene, providing a significant theoretical foundation for the pathogenesis and potential interventions underlying benzene-induced hematotoxicity.

Endocrine-disrupting chemicals (EDCs) significantly contribute to health issues by interfering with hormonal functions. Bisphenol A (BPA), a prominent EDC, is extensively utilized as a monomer and plasticizer in producing polycarbonate plastic and epoxy resins, making it one of the highest-demanded chemicals in commercial use. This is the major component used in plastic products, including bottles, containers, storage items, and food serving ware. Exposure of BPA happens through oral, respiratory, transdermal routes and eye contact. As an EDC, BPA disrupts hormonal binding, leading to various health problems, such as cancers, reproductive abnormalities, metabolic syndrome, immune dysfunction, neurological effects, cardiovascular problems, respiratory issues, and obesity. BPA mimics the hormone estrogen but exhibits a weak affinity for estrogen receptors. This weak binding affinity triggers multiple cell death pathways, including necroptosis, pyroptosis, apoptosis, ferroptosis, and autophagy, across different cell types. Numerous clinical, in-vitro, and in-vivo experiments have demonstrated that BPA exposure results in unfavorable health effects. This review highlights the mechanisms of cell death pathways initiated through BPA exposure and the associated negative health consequences. The extensive use of BPA and its frequent detection in environmental and biological models underscore the urgent need for further investigation into its effects and the development of safe alternatives. Addressing the health risks posed by BPA involves a comprehensive approach that includes reducing exposure and finding novel substitutes to lessen its detrimental impact on humans.

High-fidelity kidney function imaging is important for assessing the nephrotoxicity of drugs and diagnosing renal diseases. However, the current challenges in achieving accurate kidney imaging include unspecific signal enhancement due to albumin binding and relatively low distribution of imaging agents in kidneys. Here, for the first time, a side-chain engineering strategy that incorporates hydrophilic six-membered heterocycles into aza-hemicyanine for generating high-performance kidney imaging agents with protein-interference-free and kidney-targeting features is proposed. Based on these unique aza-hemicyanine dyes, the first kidney-targeting and albumin-insensitive H2S2 near-infrared (NIR) fluorescent probe NA-H2S2 is designed, which demonstrates effective kidney distribution following intravenous injection and is specifically activated by H2S2. The designed probe presents a highly rapid, selective and sensitive response to H2S2 with a detection limit as low as 24.21 nm. Additionally, it successfully achieves real-time in vivo NIR fluorescence imaging of H2S2 during erastin/cisplatin induced renal ferroptosis. Moreover, it also enables rapid detection of H2S2 through in vitro optical urinalysis, offering significant diagnostic value for renal ferroptosis. Overall, this study not only presents a practical kidney-targeting H2S2 fluorescent probe NA-H2S2 with increased imaging accuracy but also provides promising kidney-targeting and albumin-insensitive aza-hemicyanine dyes for further development of kidney disease-related probes.

eIF2α Phosphorylation helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. This study aims to elucidate the transcriptional regulation of glutathione (GSH) and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) homeostasis through eIF2α phosphorylation and its impact on cell death during ER stress. eIF2α phosphorylation-deficient (A/A) cells exhibited decreased expression of multiple genes involved in GSH synthesis and NADPH production, leading to an exacerbated depletion of both cellular and mitochondrial GSH, as well as mitochondrial NADPH, during ER stress. Impaired GSH homeostasis resulted from deficient expression of ATF4 and/or its dependent factor, Nrf2, which are key transcription factors in the antioxidant response during ER stress. In contrast, the exacerbation of NADPH depletion may primarily be attributed to the dysregulated expression of mitochondrial serine-driven 1-carbon metabolism pathway genes, which are regulated by an unidentified eIF2α phosphorylation-dependent mechanism during ER stress. Moreover, the eIF2α phosphorylation-ATF4 axis was responsible for upregulation of ferroptosis-inhibiting genes and downregulation of ferroptosis-activating genes upon ER stress. Therefore, ER stress strongly induced ferroptosis of A/A cells, which was significantly inhibited by treatments with cell-permeable GSH and the ferroptosis inhibitor ferrostatin-1. ATF4 overexpression suppressed impairment of GSH homeostasis in A/A cells during ER stress by promoting expression of downstream target genes. Consequently, ATF4 overexpression mitigated ferroptosis as well as apoptosis of A/A cells during ER stress. Our findings underscore the importance of eIF2α phosphorylation in maintaining GSH/NADPH homeostasis and inhibiting ferroptosis through ATF4 and unidentified eIF2α phosphorylation-dependent target(s)-mediated transcriptional reprogramming during ER stress.

Ferroptosis has been recognized as a potential treatment for various cancers. Still, in the complex tumor microenvironment, the communication between cancer cells and tumor-associated macrophages (TAMs) plays a crucial role in tumorigenesis and progression. In this work, scanning electrochemical microscopy (SECM) has been combined with microfluidic devices to enable on-chip cell coculture and in situ investigation of the communication between triple-negative breast cancer cells (TNBCs) and TAMs in ferroptosis. In the coculture system, TNBCs and TAMs were used as responding cells and signaling cells, respectively. By in situ monitoring the changes of key parameters (ROS, glutathione (GSH), and cell membrane permeability) in Erastin-induced ferroptosis, it was found that TAMs partially restored the reduced GSH efflux, increased ROS release, and impaired cell membrane barrier in TNBCs, indicating that TAMs can suppress TNBC ferroptosis. Mechanistically, TNBCs could promote M2 macrophage polarization, and M2-TAMs achieved suppression of TNBCs ferroptosis through the STAT3-related signaling pathway. After inhibition of STAT3, increased ROS release and membrane permeability as well as decreased GSH efflux of TNBCs were in situ monitored by SECM, demonstrating the intercellular communication mechanism in ferroptosis. Therefore, this work provides a potential strategy of targeting TAMs for ferroptosis-based TNBC therapy.

Glaesserella parasuis cytolethal distending toxin (GpCDT) is a bacterial genotoxin whose main action is to activate DNA damage responses, induce cell cycle arrest, and induce the apoptosis of host cells. In our previous studies, we reported that cells incubated with GpCDT exhibited changes in the expression of ferroptosis-related proteins; thus, we hypothesized that, in addition to apoptosis, GpCDT may also cause ferroptosis, a novel mode of cell death. Here, we observed that treatment of 3D4/21 cells with GpCDT resulted in cytoplasmic iron overload, depletion of GSH (reduced glutathione), and overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA), indicating that GpCDT disrupted iron metabolism and redox homeostasis in these cells. These phenomena were counteracted by the specific ferroptosis inhibitor ferrostatin-1 and the iron chelator deferoxamine mesylate. In vitro infection with the Glaesserella parasuis field isolate strain SC1401 (CDT positive) induced changes in the expression of ferroptosis biomarkers and proteins. Infection of C57BL/6 mice yielded similar results. Our results suggest that ferroptosis may play a substantial role in GpCDT-induced cellular injury.

Ferroptosis has been reported to be involved in the occurrence and development of various kidney diseases. Emerging evidence suggests that ferroptosis also plays a critical role in systemic lupus erythematosus (SLE) and lupus nephritis (LN), contributing to podocyte injury and renal dysfunction. Mesenchymal stromal cells (MSCs) have become an attractive option for podocyte injury repairing in LN. The aim of this research was to determine whether MSCs regulate ferroptosis of podocytes in LN.

MSCs were injected into female MRL/lpr mice via tail vein. The symptoms of LN and the detection of ferroptosis-related biomarkers in podocytes were detected. In vitro validation was conducted by mouse podocyte cell line MPC-5.

The occurrence of ferroptosis and involvement of Nrf2/heme oxygenase-1 (HO-1) signaling pathway in podocytes were observed. We found increased expression of the podocyte marker, Wilm's tumor 1 (WT-1) and synaptopodin, following the improvement of lupus-like symptoms after MSC transplantation in MRL/lpr mice. The expression of ferroptosis-related protein glutathione peroxidase 4 (GPX4) and long chain acyl-CoA synthetase 4 (ACSL4) were elevated in renal, along with the Nrf2 and HO-1 activity enhancement. In vitro, MSC treatment maintain a stabilization of podocyte actin stress fibers, leading to an improvement of cell viability. Furthermore, our results showed that puromycin aminonucleoside (PAN) induce accumulation of cellular lipid reactive oxygen species (ROS) and glutathione depletion, and the expression of Nrf2, HO-1 and GPX4 were all downregulated whereas the expression of ACSL4 was upregulated. However, these effects were reversed by MSCs and ferroptosis inhibitor ferrastatin-1 (Fer-1). The promotion of Nrf2 nuclear translocation was observed after the treatment with MSCs.

Ferroptosis activation is involved in the development of LN. MSCs could ameliorate podocyte injury in LN by inhibiting ferroptosis through the Nrf2/HO-1/GPX4 pathway, which will provide novel potential therapeutic targets for LN.

Multiple myeloma (MM) is a highly malignant hematological tumor with a low overall survival rate, making the identification of innovative prognostic markers essential due to its complex and heterogeneous nature. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, is now recognized as crucial in tumor development and progression. Consequently, ferroptosis-related genes (FRGs) are emerging as promising therapeutic targets and prognostic indicators. However, the specific roles and predictive value of FRGs in MM still remain unclear. The current study was therefore conceived to examine the possible involvement of FRGs in MM. FRGs data was obtained from the FerrDb resource. The datasets GSE133346 and GSE166122, sourced from the Gene Expression Omnibus (GEO), provided gene expression data for both healthy and MM individuals. The differentially expressed-FRGs (DE-FRGs) were identified using the limma and DESeq2 packages in R. Functional pathways were analyzed through Gene Ontology (GO) and KEGG enrichment analyses. The miRWalk database was used for miRNA association and enrichment analysis with hub genes. Prognosis-related genes were evaluated using Kaplan-Meier survival analyses. We identified 1400 differentially expressed genes and cross-referenced them with FRGs, ultimately selecting 17 as DE-FRGs or hub genes. GO analysis revealed that the primary enriched functions of these hub genes are sister chromatid segregation, condensed chromosome centromeric region, C-C chemokine receptor activity, and C-C chemokine binding. KEGG pathway analysis showed that these overlapped genes were enriched in several pathways, including cell cycle, viral protein interaction with cytokine and cytokine receptor, as well as breast and prostate cancers involved pathways. Furthermore, significant enrichment was observed in glycolysis, gluconeogenesis, and the citrate cycle pathways based on miRNAs association with the candidate genes. The CAV1, CD44, TFRC, DPP4, and GJA1 are identified as top five significant hub DE-FRGs based on protein-protein interaction (PPI) analysis from multiple resources. Survival analysis eventually identified CAV1, CD44, and TFRC as the top-ranked DE-FRGs associated with overall survival, underscoring their crucial role in MM. This study identifies CAV1, CD44, and TFRC as key FRGs associated with the prognosis of MM, suggesting their potential as valuable prognostic markers and therapeutic targets to improve patient outcomes.

Diabetic cardiomyopathy (DCM) is an important complication of chronic diabetes mellitus. However, its pathologic process and pathogenesis have not been fully elucidated. This study aims to investigate the role of ferroptosis in DCM and clarify the effect of heme oxygenase-1 (HMOX1) on DCM by targeting ferroptosis. In vivo, an animal model of DCM is established by subjecting mice to a high-fat diet (HFD) combined with low-dose streptozotocin (STZ) injection. We induce an in vitro DCM model by exposing H9C2 cells to high glucose and palmitic acid. Transcriptome sequencing reveals that the differentially expressed genes (DEGs) are enriched primarily in fatty acid metabolism and mitochondrial fatty acid β-oxidation, which are closely related to ferroptosis. The experimental results show that the diabetic microenvironment induces ferroptosis both in vivo and in vitro. Western blot analysis reveals the decreased expressions of the antioxidant proteins GPX4, SLC7A11 and ferritin in the DCM group. However, qPCR demonstrates the elevated expressions of the ferroptosis markers PTGS2 and ACSL4. Biochemical indicators further support the occurrence of ferroptosis, with increased levels of malondialdehyde (MDA) and lactate dehydrogenase (LDH), along with decreased level of glutathione (GSH). In vitro, intervention with high glucose and palmitic acid in H9C2 cells results in ferroptosis, which is reversed by ferrostatin-1 (Fer-1). Results show the elevated expression of HMOX1 in DCM. Moreover, knockdown of HMOX1 ameliorates ferroptosis, thereby alleviating diabetic cardiomyopathy by reducing cardiac fibrosis and improving cardiac function. Our study elucidates the role of HMXO1 in DCM pathogenesis and provides a potential therapeutic strategy for clinical treatment.

Malignancies of the oral cavity, oropharynx, hypopharynx, and larynx rank as the seventh most prevalent cancers globally, characterized by high morbidity and mortality. Despite advancements in conventional therapies, these cancers often demonstrate recurrence and treatment resistance. This review investigates ferroptosis, an iron-dependent regulated cell death mechanism, as a novel therapeutic target to overcome resistance and recurrence in these cancers. A narrative review study was conducted using online databases, including PubMed, Google Scholar, Scopus, and Web of Science. The search incorporated keywords such as "ferroptosis", "oral squamous cell carcinoma", "oropharyngeal cancer", "hypopharyngeal cancer", "laryngeal cancer", "iron metabolism", and "lipid peroxidation". Studies focusing on molecular mechanisms, ferroptosis regulation, and therapeutic applications were included. Key findings highlighted the involvement of genes like CA9, CAV1, and SLC7 A11 in oral squamous cell carcinoma (OSCC), contributing to progression and resistance. Ferroptosis inducers such as resveratrol and quercetin effectively promoted ferroptosis in OSCC by targeting pathways like p53/SLC7 A11. In hypopharyngeal and oropharyngeal cancers, agents like ascorbic acid and RSL3 enhanced lipid peroxidation, while laryngeal cancers showed resistance through molecules like SLC3 A2 and KPNA2, which could be counteracted with targeted therapies. Nanotechnology-based approaches, including photodynamic therapy and nanofiber membranes, offer potential for localized and effective ferroptosis induction. Ferroptosis holds promise as a therapeutic strategy for treating head and neck cancers by addressing treatment resistance and recurrence. Future research should focus on optimizing combination therapies, understanding molecular heterogeneity, and translating preclinical findings into clinical applications to improve patient outcomes.

Traumatic brain injury (TBI) remains a major cause of mortality and long-term disability worldwide, with ferroptosis and necroptosis emerging as key drivers of secondary neuronal damage. Ferroptosis, characterized by iron-dependent lipid peroxidation and mitochondrial dysfunction, exacerbates oxidative stress and neuronal cell death. In parallel, necroptosis, mediated by receptor-interacting protein kinases (RIPK1 and RIPK3), amplifies inflammation through membrane rupture and the release of cellular components. Mitochondrial dynamics, involving fission and fusion processes, play a dual role in regulating these pathways. While mitochondrial fusion preserves cellular integrity and reduces oxidative stress, excessive mitochondrial fission driven by dynamin-related protein 1 (DRP1) accelerates necroptotic signaling and neuronal injury. This intricate interplay between ferroptosis, necroptosis, and mitochondrial dynamics highlights potential therapeutic targets. Modulating these pathways through tailored interventions could reduce neuronal damage, mitigate neuroinflammation, and improve functional outcomes in TBI patients. Advancing our understanding of these mechanisms is essential for developing precision therapies that address the complex pathology of traumatic brain injury.

Lung cancer remains the leading cause of cancer-related deaths worldwide, with increasing attention being given to novel therapeutic strategies that target the mechanisms underlying tumor growth and drug resistance. Among these, ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation, has become a key focus in cancer research. Despite extensive research, the exact role of ferroptosis in lung cancer progression and treatment remains unclear, especially regarding its interaction with immune cells and the tumor microenvironment.

To address these limitations, this study utilizes a comprehensive bibliometric analysis to explore the current landscape of ferroptosis research in lung cancer. We collected data from the Web of Science Core Collection, covering articles published between 2015 and 2025, and analyzed them using advanced tools such as VOSviewer and CiteSpace.

This study uses a comprehensive bibliometric analysis to uncover key trends and emerging areas related to lung cancer in ferroptosis research. Recently, the focus has shifted from basic mechanisms to clinical applications, particularly in developing GPX4-targeted therapies and combination treatments. With increasing international collaboration, the United States and China have become key players. Interdisciplinary research, especially on ferroptosis and the cancer-immune system, offers new insights into its role in the tumor microenvironment and immunotherapy. Ferroptosis shows excellent promise in overcoming drug resistance by regulating iron-dependent lipid peroxidation and enhancing treatment efficacy. Future research should focus on ferroptosis' clinical translation, particularly in personalized medicine and overcoming resistance, offering broad prospects for lung cancer treatment.

This paper provides valuable insights into the trends, key contributors, and emerging frontiers of ferroptosis research in lung cancer. It identifies important developments that can serve as a foundation for translating ferroptosis-based therapies into clinical practice, particularly to address drug resistance in lung cancer.

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

Ferroptosis is an important regulated cell death mechanism characterized by iron-dependent lipid peroxidation and oxidative stress. In this study, we examined the ferroptosis-inducing effect of the combined use of Paclitaxel, a microtubule-stabilizing agent, and Erastin, a ferroptosis inducer, in breast cancer cells. In this context, the combination of the compounds in question was applied to the cells and the presence of a synergistic effect was determined by calculating the combination index. Glutathione (GSH) levels and glutathione peroxidase (GPX) activity were determined by commercial assay kits, and the effect of the compounds on lipid peroxidation was determined by measurement of malondialdehyde (MDA) levels. Additionally, the effect of combination treatment on ferroptotic protein expression was determined by western blot. Our findings revealed that the combination treatment caused a significant change in mitochondrial function by causing an increase in the depolarized/viable cell population. Additionally, there was a significant increase in intracellular reactive oxygen species (ROS) levels compared to single applications of the compounds. The significant increase observed in malondialdehyde (MDA) levels revealed that the combination treatment increased lipid peroxidation. Moreover, intracellular GSH levels and glutathione peroxidase (GPX) activity significantly decreased by Paclitaxel-Erastin combination. The expression of ferroptosis-regulating proteins was significantly downregulated. The findings showed that the Paclitaxel-Erastin combination synergistically contributed to the accumulation of lipid reactive oxygen species and induced the ferroptotic cell death pathway in breast cancer cells.

Ferroptosis is recently discovered as an important player in the initiation, proliferation, and progression of human tumors. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) has been reported as an oncogene in multiple types of cancers, including lung adenocarcinoma (LUAD). However, little research has been designed to investigate the regulation of IGF2BP3 on ferroptosis in LUAD. qRT-PCR and western blot were used to measure the mRNA and protein expression of IGF2BP3 and transcription factor AP-2 alpha (TFAP2A). CCK-8 assay was performed to determine cell viability. DCFH-DA and C11-BODIPY staining were used to detect the levels of intracellular reactive oxygen species (ROS) and lipid ROS. The corresponding assay kits were used to analyze the levels of malondialdehyde (MDA) and glutathione (GSH). SRAMP website and m6A RNA immunoprecipitation (Me-RIP) were used to predict and confirm the m6A modification of TFAP2A. RIP experiments were conducted to confirm the binding of IGF2BP3 and TFAP2A. RNA stability assay was performed using actinomycin D. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter experiments were performed to confirm the interaction between TFAP2A and cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4). Mice xenotransplant model was also constructed to explore the effect of IGF2BP3 on LUAD tumor growth and ferroptosis. IGF2BP3 and TFAP2A were both highly expressed in LUAD. IGF2BP3 or TFAP2A knockdown induced ferroptosis by aggravating erastin-induced cell viability suppression, increasing the production of intracellular ROS, lipid ROS, and MDA, and decreasing GSH synthesis, GSH/GSSG ratio, and cystine uptake. Mechanistically, IGF2BP3 stabilized TFAP2A expression via m6A modification. Moreover, sh-IGF2BP3-mediated ferroptosis was significantly abated by TFAP2A overexpression. Furthermore, TFAP2A binds to the promoters of SLC7A11 and GPX4 to promote their transcription. Also, IGF2BP3 depletion suppressed LUAD tumor growth by inducing ferroptosis in mice. IGF2BP3 suppresses ferroptosis in LUAD by m6A-dependent regulation of TFAP2A to promote the transcription of SLC7A11 and GPX4. Our findings suggest that targeting IGF2BP3/TFAP2A/SLC7A11/GPX4 axis might be a potential therapeutic choice to increase ferroptosis sensitivity in LUAD.

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

Patients with osteosarcoma (OS) exhibit metastasis upon diagnosis, and the condition frequently acquires resistance to traditional chemotherapy treatments, failing the therapy. The objective of this research was to examine the impact of curculigoside (Cur), a key phenolic compound discovered in the rhizome of C. orchioides Gaertn, on OS cells and the surrounding tumor environment.

We assessed the impact of curculigoside on tumor inhibition in four osteosarcoma cell lines and mice tumor xenograft models using various techniques including cell viability assay, wound healing assay, cell apoptosis analysis, immunofluorescent staining, and IHC. Moreover, we created a mini-PDX model by utilizing freshly obtained primary OS cells from surgically removed OS tissues to evaluate the possible clinical use of Cur.

The results of our study show that Cur triggers cell death in OS cells and enhances the maturation of RAW264.7 cells. By effectively inhibiting the growth of OS cells, these actions mechanistically trigger the catastrophic buildup of unbound iron and uncontrolled lipid peroxidation, ultimately resulting in ferroptosis. Moreover, additional validation of Cur's substantial antineoplastic impact is obtained through in vivo experiments employing xenograft and mini-PDX models.

To sum up, this research is the initial one to exhibit the anti-tumor effects of Cur on OS using various methods, indicating that Cur shows potential as a viable approach for treating OS.

Sepsis-induced liver injury (SILI) is a severe complication of sepsis. Wedelolactone (WEL) can be used to treat liver diseases. However, its therapeutic mechanisms and efficacy in SILI remain unclear. To investigate the therapeutic effects of WEL on SILI and its potential mechanisms of action through in vitro and in vivo experiments.

A SILI model based on lipopolysaccharide (LPS), and AML12 cells were treated with different concentrations of WEL, LY294002 and ML385. The SILI model was established by caecal ligation and puncture (CLP). C57BL/6 mice were administered WEL and biphenyl diester for seven consecutive days, and CLP was then performed 1 h later. Blood and liver tissue were collected 24 h later for subsequent analysis. HE staining, liver function index, oxidative stress index, JC-1 staining, transmission electron microscopy, immunofluorescence staining, Western blot, and inflammatory cytokines were used to detect oxidative stress and ferroptosis-related markers.

The in vivo experiments showed that WEL treatment reduced the pathological damage of the liver and decreased ALT and AST, MMP and ROS (the product of iron and lipid peroxidation) and inflammatory factors. WEL also decreased hepatocyte viability in vitro. Inhibition of NRF2 can lead to exacerbation of SILI. The expressions of P-PI3K and P-AKT were up-regulated while HO-1, GPX4, NRF2, and SLC7A11 were down-regulated in vitro and in vivo.

Ferroptosis and oxidative stress are pivotal in SILI. WEL mitigates SILI by inhibiting ferroptosis and oxidative stress, primarily through the PI3K/AKT/NRF2 and SLC7A11/GPX4 signalling pathways, thus suggesting a promising therapeutic strategy.

Background: Finding effective strategies and novel targets for reversing drug resistance is one of the major frontiers in hepatocellular carcinoma (HCC) research. Ferroptosis is participate in the malignant progression and drug resistance of HCC. However, the underlying molecular mechanisms remail largely uninvestigated. Methods: HCC cell lines and xenografted nude mice were used as experimental models. Biological functions were investigated by various molecular biology experiments. An HCC population was used to reveal clinical significance. Results: In our study, HCG18 and RRM2 was found to be associated with unfavorable prognosis. HCG18 regulates RRM2 expression through competitively binding to miR-30a-5p, consequently impacting ferroptosis. RRM2 directly regulated GSS to increase GSH synthesis. The colony formation assay demonstrated that overexpression of HCG18 inhibited erastin-induced cell death. In addition, in vivo experiments have also confirmed that HCG18 can inhibit ferroptosis by regulating the expression of RRM2, thereby promoting HCC proliferation. Conclusion: Our study discovered a novel lncRNA HCG18, as a "switch-like" molecule of the axis of miR-30a-5p/RRM2/GSS, confers resistance to ferroptosis and holds promise as a potential target for ferroptosis-dependent therapy.

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

Amino acid metabolism constitutes a major metabolic pathway in plants, playing an important role in the modulation of plant responses to stress. In this study, we investigated the amino acid metabolism responses of M. sativa (Medicago sativa L.) and M. truncatula (Medicago truncatula L.) plants under salt stress using transcriptomic and proteomic approaches to elucidate their salt stress tolerance mechanisms in relation to the regulation of amino acid homeostasis. Transcriptome and proteome sequencing followed by Kyoto Gene and Genome Encyclopedia enrichment analysis revealed 34 differentially expressed genes and 45 differentially expressed proteins involved in valine, leucine, and isoleucine degradation, tyrosine metabolism, and glutathione metabolism. Significant differences were observed in the expression of glutathione S-transferase (GST) within the glutathione metabolic pathway between M. sativa and M. truncatula. The induction of valine, leucine, and isoleucine metabolism, aldehyde dehydrogenases (ALDHs), and alanine-glyoxylate aminotransferases (AGXTs), involved in intracellular reactive oxygen species scavenging, also significantly differed under salt stress. Significant differences were identified in the expression of tyrosine decarboxylases (TDCs) involved in tyrosine metabolism, which are responsible for tyramine biosynthesis and can enhance plant tolerance to salt stress. This study delved into the effects of amino acid metabolism on the salt tolerance mechanisms of M. sativa and M. truncatula, which is crucial in guiding the future breeding of salt-tolerant alfalfa varieties.

Hepatoblastoma (HB) is a rare but predominant liver cancer in children, with few treatment choices in advanced stages. YWHAE is closely related to several human diseases and acts as a molecular scaffold for malignant transformation. However, whether YWHAE promotes HB development remains unknown. Conducting RNA and m6A sequencing on HB tissues, we found that YWHAE was upregulated and modified by N6-methyadenosine. Functionally, YWHAE promoted proliferation and inhibited cell death in HB by in vitro and in vivo studies. Mechanistically, METTL3-dependent m6A modification activated YWHAE mRNA expression, and the m6A reader IGF2BP2 recognized and bound to the m6A site on YWHAE mRNA, thereby enhancing the mRNA stability of YWHAE. Interestingly, RNA sequencing revealed that YWHAE knockdown was involved in regulating ferroptosis of HB cells by mediating SLC7A11 expression. Moreover, knockdown of YWHAE significantly increased the levels of lipid ROS and peroxides in HB cells, promoting the susceptibility of HB cells to ferroptosis. In summary, these findings illuminated the role of YWHAE in HB progression and uncovered its relevance to ferroptosis as a new therapeutic target for HB.

High-Grade Serous Ovarian Cancer (HGSOC) is the most common and lethal subtype of ovarian cancer, known for its high aggressiveness and extensive genomic alterations. Typically diagnosed at an advanced stage, HGSOC presents formidable challenges in drug therapy. The limited efficacy of standard treatments, development of chemoresistance, scarcity of targeted therapies, and significant tumor heterogeneity render this disease incurable with current treatment options, highlighting the urgent need for novel therapeutic approaches to improve patient outcomes. In this study we report a straightforward and stereoselective synthetic route to novel Pd(II)-vinyl and -butadienyl complexes bearing a wide range of monodentate and bidentate ligands. Most of the synthesized complexes exhibited good to excellent in vitro anticancer activity against ovarian cancer cells. Particularly promising is the water-soluble complex bearing two PTA (1,3,5-triaza-7-phosphaadamantane) ligands and the Pd(II)-butadienyl fragment. This compound combines excellent cytotoxicity towards cancer cells with substantial inactivity towards non-cancerous ones. This derivative was selected for further studies on ex vivo tumor organoids and in vivo mouse models, which demonstrate its remarkable efficacy with surprisingly low collateral toxicity even at high dosages. Moreover, this class of compounds appears to operate through a ferroptotic mechanism, thus representing the first such example for an organopalladium compound.

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

Renal ischemia‒reperfusion (I/R) injury is the main cause of acute kidney injury, and its pathological features are manifested primarily by renal tubular epithelial cell injury. The underlying mechanism involves ferroptosis of renal tubular epithelial cells. Atorvastatin (ATO) regulates ferroptosis, and this study explored its role in I/R-induced ferroptosis of renal tubular epithelial cells. We constructed a renal I/R rat model with bilateral renal pedicles using noninvasive arterial clips and placed HK-2 cells in hypoxia/reoxygenation (H/R) incubators to construct the cell model. The damage to rat kidney tissues and HK-2 cells was assessed using enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (H&E) staining, and flow cytometry, and the presence of associated proteins was identified through western blotting. Administering ATO markedly lessened the acute kidney damage caused by I/R, decreased the levels of blood urea nitrogen (BUN) and creatinine (CRE), and prevented apoptosis in renal tubular epithelial cells. Treatment with ATO additionally suppressed the production of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and markers linked to ferroptosis (Fe2+, ROS, MDA, ACSL4, and COX2), thereby reducing acute kidney damage associated with I/R. The expression of PGE2 in renal I/R injury is related to the degree of renal injury, and it mainly regulates ferroptosis by binding to EP4. ATO effectively inhibited the expression of PGE2 and EP4. Overall, this study revealed that ATO inhibited ferroptosis of renal tubular epithelial cells by blocking the PGE2/EP4 signaling pathway, thereby alleviating I/R-induced kidney injury.

Colorectal cancer (CRC) is one of the most prevalent and life-threatening malignancies worldwide. Jujuboside B (JUB) is a bioactive compound derived from the seeds of Ziziphus jujuba, known for its potential anticancer properties. The present study aimed to investigate the association of JUB with inhibiting the proliferation, apoptosis and ferroptosis of human CRC cells with mitogen-activated protein kinase (MAPK) pathway regulation. First, the human CRC HCT116 cell line was treated with different concentrations of JUB. Subsequently, cell viability was evaluated using MTT assay and colony formation was assessed using a colony formation assay. Flow cytometry was used to detect cell apoptosis and the levels of reactive oxygen species. Western blotting was utilized to assess the expression levels of apoptosis-related proteins, ferroptosis regulators and MAPK pathway-related proteins. In addition, biochemical assay kits were used to evaluate the levels of malondialdehyde, glutathione, total iron and ferrous iron. The results demonstrated that cell viability and colony formation were markedly decreased after JUB treatment, whilst the level of apoptosis was notably increased in a concentration-dependent manner. Using electron microscopy, cells treated with JUB exhibited typical apoptotic bodies, as well as mitochondrial swelling and cristae disruption, further demonstrating JUB-induced cell apoptosis. Western blot analysis indicated that JUB treatment markedly reduced the expression of B-cell lymphoma-2 (Bcl-2) but notably increased the expression of Bcl-2 associated X-protein and cleaved caspase-3. Additionally, JUB induced ferroptosis and inhibited the MAPK signaling pathway in CRC cells. Collectively, the findings of the present study suggest that JUB has the potential to inhibit CRC cell proliferation and induce apoptosis through regulating the MAPK pathway. Therefore, JUB may be a promising therapeutic agent for the treatment of CRC.