Hearing loss profoundly affects social engagement, mental health, cognition, and brain development, with sensorineural hearing loss (SNHL) being a major concern. Linked to ototoxic medications, ageing, and noise exposure, SNHL presents significant treatment challenges, highlighting the need for effective prevention and regeneration strategies. Ferroptosis, a distinct form of cell death featuring iron-dependent lipid peroxidation, has garnered interest due to its potential role in cancer, ageing, and neuronal degeneration, especially hearing loss. The emerging role of ferroptosis as a crucial mediator in SNHL suggests that it may offer a novel therapeutic target for otoprotection. This review aims to summarise the intricate connection between ferroptosis and SNHL, offering a fresh perspective for exploring targeted therapeutic strategies that could potentially mitigate cochlear cells damage and enhance the quality of life for individuals with hearing impairments.

Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates many critical genes associated with iron storage and transportation, the activity of which is influenced by E3 ligase-mediated ubiquitination. We wondered whether there is a deubiquitinase that mediates the deubiquitination of Nrf2 to stabilize Nrf2 expression and further prevent diabetic kidney disease (DKD). High glucose (HG) was applied to induce an in vitro model of DKD. The effects of HG on HK-2 cell viability, apoptosis, Fe2+ level, Nrf2, and ubiquitin-specific protease 9X (USP9X) were assessed by cell counting kit-8 (CCK-8) assay, flow cytometry, iron assay, and Western blot. The direct interaction between Nrf2 and USP9X was analyzed using co-immunoprecipitation and ubiquitination assay. After transfection and ferrostatin-1 (Fer-1) intervention, Nrf2 and USP9X levels, cell viability, apoptosis, and Fe2+ level were tested again. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) contents, and ferroptosis-related markers were assessed by ROS assay kit, ELISA, and Western blot. HG reduced cell viability and levels of USP9X and Nrf2, while elevating apoptosis and Fe2+ level. An interaction between USP9X and Nrf2 has been verified and USP9X deubiquitinated Nrf2. Nrf2 up-regulation augmented the viability, GSH content, and ferroptosis-related protein expressions, while suppressing the apoptosis, Fe2+ level, MDA, and ROS content in HG-mediated HK-2 cells, which was reversed by USP9X silencing. Fer-1 offset the combined modulation of Nrf2 and siUSP9X on HG-induced HK-2 cells. USP9X mediates Nrf2 deubiquitinase to hamper the ferroptosis in DKD in vitro.

The cGAS-STING pathway plays an important role in ischemia-reperfusion injury in the heart, liver, brain, and kidney, but its role and mechanisms in cerebral ischemia-reperfusion injury have not been systematically reviewed. Here, we outline the components of the cGAS-STING pathway and then analyze its role in autophagy, ferroptosis, cellular pyroptosis, disequilibrium of calcium homeostasis, inflammatory responses, disruption of the blood-brain barrier, microglia transformation, and complement system activation following cerebral ischemia-reperfusion injury. We further analyze the value of cGAS-STING pathway inhibitors in the treatment of cerebral ischemia-reperfusion injury and conclude that the pathway can regulate cerebral ischemia-reperfusion injury through multiple mechanisms. Inhibition of the cGAS-STING pathway may be helpful in the treatment of cerebral ischemia-reperfusion injury.

Gas explosion injuries are a severe form of trauma with high incidence and mortality rates, both in daily life and industrial settings. Acute lung injury (ALI) is one of the most serious complications of gas explosion injuries and is a leading cause of mortality in such cases. However, the mechanisms underlying gas explosion-induced ALI have not been fully elucidated, and the treatment process consumes a significant amount of medical resources. Therefore, it is crucial to conduct research on the injury mechanisms of gas explosion injuries, especially the mechanisms of gas explosion-induced ALI, which can effectively improve the treatment rate of this condition. In this study, we analyzed the relationship between a novel form of cell death, ferroptosis, and gas explosion-induced ALI, and explored its specific mechanisms.

We established ALI rat model by Shock tube biological injury system, and detected lung injury-related indexes as well as ferroptosis related indexes, such as glutathione peroxidase 4（GPX4）, 4-hydroxynonenal（4HNE）, Malondialdehyde（MDA）, Fe2 + . We also investigated the therapeutic effects of the ferroptosis inhibitor ferrostatin-1 (Fer-1) in ALI induced by gas explosion, as well as its specific mechanisms of action.

A rat ALI model by gas explosion was successfully established. After the gas explosion treatment, we observed that the systemic inflammatory reaction of rats was increased, and lung function, liver function, kidney function and cardiac function were damaged to different degrees. The inflammatory infiltration in the lung tissue was more severe, and the degree of lung injury and pulmonary edema increased. The ferroptosis markers GPX4 was decreased, while the levels of 4HNE, MDA and Fe2 + were increased. Treatment with Fer-1 significantly ameliorated gas explosion ALI damage and down-regulated the expression level of ferroptosis.

Gas explosion-induced ALI in rats is characterized by enhanced inflammatory responses and reduced antioxidant capacity in lung tissues. The specific mechanism of injury involves ferroptosis. Fer-1 has been shown to mitigate the severity of ALI caused by gas explosion by suppressing ferroptosis expression levels in lung tissues via the Nrf2/GPX4 axis.

COVID-19 is a human respiratory syndrome caused by the infection of the SARS-CoV-2 virus that has a high rate of infection and mortality. Viruses modulate the host machinery by altering cellular mechanisms that favor their replication. One of the mechanisms that viruses exploit is the protein folding and processing of post-translational modifications that occur in the endoplasmic reticulum (ER). When ER function is impaired, there is an accumulation of misfolded proteins leading to endoplasmic reticulum stress (ER stress). To maintain homeostasis, cells trigger an adaptive signaling mechanism called the Unfolded Protein Response (UPR) which helps cells deal with stress, but under severe conditions, can activate the apoptotic cell death mechanism. This study elucidated an activation of a diversity of molecular mechanisms by Brazilian variants of SARS-CoV-2 by a time-resolved and large-scale characterization of SARS-CoV-2-infected cells proteomics and immunoblotting. Furthermore, it was shown that pharmacological UPR modulation could reduce viral release by counteracting the different viral activations of its cellular response. Analysis of human clinical specimens and disease outcomes focusing on ER stress reinforces the importance of UPR modulation as a host regulatory mechanism during viral infection and could point to novel therapeutic targets. SIGNIFICANCE: Since the emergence of SARS-CoV-2 and the consequent COVID-19 pandemic, the rapid emergence of variants of this new coronavirus has been a cause for concern since many of them have significantly higher rates of transmissibility and virulence, being called Variants of Concern (VOC). In this work, we studied the VOCs Gamma (P.1) and Zeta (P.2), also known as Brazilian variants. Constant evidence has reported that there are particularities related to each variant of SARS-CoV-2, with different rates of transmissibility, replication and modulation of host biological processes being observed, in addition to the mutations present in the variants. For this reason, this work focused on infections caused by the Brazilian variants of SARS-CoV-2 in different cell lines, in which we were able to observe that the infections caused by the variants induced endoplasmic reticulum stress in the infected cells and activated the UPR pathways, presenting specific modulations of each variant in this pathway. Furthermore, transcriptome analysis of patients revealed a correlation between ER-related genes and COVID-19 progression. Finally, we observed that the use of UPR modulators in host cells decreased viral release of all variants without affecting cell viability. The data presented in this work complement the observations of other studies that aim to understand the pathogenicity of SARS-CoV-2 VOCs and possible new therapeutic strategies, mainly targeting biological processes related to the endoplasmic reticulum.

Sepsis is a life‑threatening organ dysfunction disorder caused by dysfunctional host response to infection. Sepsis‑induced cardiomyopathy (SIC) is a common and serious complication of sepsis, and it is associated with increased mortality rates; however, its specific pathogenesis is still unclear. Ferroptosis, which is an iron‑dependent form of programmed cell death, is involved in the pathophysiology of SIC. Further study on the mechanism and therapeutic targets of ferroptosis in SIC may provide new strategies for clinical diagnosis and treatment of this condition. The present article reviews the mechanisms between SIC and ferroptosis, summarizes the progress in research of the involvement of ferroptosis in SIC and provides new potential strategies for further research and treatment in the future.

Alzheimer's disease (AD) is a degenerative disease of the central nervous system, characterized by a gradual decline in cognitive and memory abilities, social disorders, and behavioral abnormalities. Ferroptosis, an iron-dependent type of programmed cell death, is closely associated with the pathogenesis of AD. Ferroptosis is characterized by the accumulation of iron within cells, leading to increased oxidative stress, and ultimately lipid peroxidation and cell death. Ganoderic acid A (GAA), one of the major pharmacologically active components in Ganoderma lucidum, exhibits an excellent neuroprotective effect against AD. However, it is unclear whether GAA improves the symptoms of AD by inhibiting ferroptosis. This study investigated the anti-AD effects of GAA through both in vivo and in vitro experiments, and determined its molecular mechanism from the perspective of ferroptosis modulation. The results showed that GAA administration attenuated hippocampal neuronal loss, improved mitochondrial ultrastructure, and enhanced the memory and learning ability of the AD mice. In vitro assays suggested that GAA effectively protected HT22 AD cells against ferroptosis-related morphological damage, enhanced their antioxidant capacity, maintained their iron metabolism, and reduced mitochondrial dysfunction. Moreover, the immunofluorescence and western blotting results showed that the levels of NFE2 like bZIP transcription factor 2 (NRF2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) both in the hippocampus of APP/PS1 mice and amyloid beta (Aβ)25-35-induced HT22 AD cells were markedly enhanced after GAA administration. In summary, these results revealed that GAA improves AD by activating on the NRF2/SLC7A11/GPX4 axis to inhibit ferroptosis-lipid peroxidation.

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.

Atherosclerosis (AS) is a lipid disorder characterised by lipid accumulation in the aortic wall and foam cell formation. Recent studies have shown that excess iron accelerates AS progression and foam cell formation by inducing ferroptosis. GPx4, an anti-erroptotic protein, promotes SCARB1 expression, which inhibits macrophage foam cell formation by interacting with HDL. Thus, a complex association exists between ferroptosis and lipid metabolism. However, the underlying mechanisms remain unclear. AMPK signalling is a key regulator of metabolism and is involved in the regulation of ferroptosis. In this study, we used the ferroptosis inhibitor ferrostatin-1 (Fer-1) to assay the effect of ferroptosis inhibition on AS and foam cell formation and to investigate the underlying mechanism. Our results showed that Fer-1 alleviated AS lesions and foam cell formation both in vivo and in vitro. Additionally, Fer-1 reduced iron content and lipid accumulation in oxidized low-density lipoprotein (ox-LDL)-treated macrophages by upregulating the levels of FTH, GPx4, and SCARB1 via AMPK activation. The inhibition of AMPK reduces the effect of Fer-1 on iron and lipid accumulation in macrophages, which may contribute to a deeper understanding of the pathological process of AS and provide a therapeutic target for AS.

Ischemic stroke (IS) continues to be a major public health concern and is characterized by significantly high mortality and disabling rates. Inhibiting nerve cells death and enhancing the repair of ischemic tissue are important treatment concepts for IS. Currently, the mainstream treatment strategies mainly focus on short-term care, which underscores the urgent need for novel therapeutic strategies for long-term care. Emerging data reveal that flavonoids have surfaced as promising candidates for IS patients' long-term care. Flavonoids can alleviate neuroinflammation and anti-apoptosis due to their characteristic pharmacological mechanisms. Clinical evidence suggests that long-term flavonoids intake improves IS patients' long-term outcomes. Though the effect of flavonoids in IS treatment has been explored for decades, the neuroprotective pharmacodynamics have not been well established. Thereby, the aim of current review is to summarize the pathways involved in neuroprotective effect of flavonoids. This review will also advance the potential of flavonoids as a viable clinical candidate for the treatment of IS.

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

Insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 2 (IGF2BP2) is a widely studied N6-methyladenosine (m6A) modification reader, primarily functioning to recognize and bind to m6A modification sites on the mRNA of downstream target genes, thereby enhancing their stability. Previous studies have suggested that the IGF2BP2-m6A modification plays an essential role in cellular functions and the progression of various diseases. In this review, we focus on summarizing the molecular mechanisms by which IGF2BP2 enhances the mRNA stability of downstream target genes through m6A modification, thereby regulating cell ferroptosis, epithelial-mesenchymal transition (EMT), stemness, angiogenesis, inflammatory responses, and lipid metabolism, ultimately affecting disease progression. Additionally, we update the related research progress on IGF2BP2. This article aims to elucidate the effects of IGF2BP2 on cell ferroptosis, EMT, stemness, angiogenesis, inflammatory responses, and lipid metabolism, providing a new perspective for a comprehensive understanding of the relationship between IGF2BP2 and cell functions such as ferroptosis and EMT, as well as the potential for targeted IGF2BP2 therapy for tumors and other diseases.

Sanghuangporus, the dried fruiting body of Sanghuangporus vaninii (Ljub) L.W.Zhou et Y.C.Dai. As the main species of Sanghuang, it has been well-known and used commonly as a traditional medicinal and edible macrofungi for thousands of years in many countries, including China, Korea and Japan. Although it has good hepatoprotective activity, its potential efficacy and mechanism on liver fibrosis remain elusive.

Total Sanghuangporus vaninii extract (TSH) was prepared by ethanol extraction to investigate its chemical components and to conduct an initial assessment of its efficacy and underlying mechanism in a murine model of liver fibrosis.

The chemical components of TSH were initially analyzed by UHPLC-Q-Orbitrap HRMS. To elucidate the effects of TSH, an in vivo model of fibrosis was established in mice using carbon tetrachloride (CCl4), followed by assessments of serum liver function and histopathological analysis. Besides, indicators related to liver fibrosis, hepatic stellate cells (HSCs) activation, inflammation response and ferroptosis related indicators were detected by western blotting, immunohistochemistry and real-time quantitative PCR (RT-qPCR) analysis. Additionally, the 16S rDNA sequencing and untargeted metabolomics analysis of intestinal microbiota were employed to investigating the role of TSH in gut microbiome. In vitro, the human hepatocyte line L02 was stimulated with erastin and treated with or without TSH to elucidate its underlying mechanism.

The administration of TSH significantly improved serum indicators of liver injury in CCl4-induced fibrosis mice, reduced HSCs activation and collagen deposition, while inhibiting the expressions of transforming growth factor-β1(TGF-β1)/Smad signaling pathway. Notably, TSH treatment attenuated hepatocyte ferroptosis and lipid peroxidation both in vivo and in vitro, as evidenced by a marked decrease in liver iron and malondialdehyde (MDA) contents. In particular, TSH was demonstrated to activate the nuclear factor erythroid 2-related factor 2 (Nrf2)-glutathione peroxidase 4 (GPX4) signaling pathway, thereby protecting hepatocytes from ferroptosis with a particular enhancement of Nrf2 nuclear transcription. Furthermore, TSH influenced gut microbiota composition and ameliorated intestinal metabolic disorders. The increased abundance of Parasutterella and Olsenellas due to TSH treatment was significantly positively correlated with elevated phosphatidylcholines involved in linoleic acid metabolism, and negatively correlated with the reduction of fatty acyls. And the enrichment of intestinal linoleic acid metabolism presented a negative correlation in liver fibrosis biomarkers.

Our findings indicate that the TSH treatment exerts a significantly protective effect on CCl4-induced mice by ameliorating hepatic injury and ferroptosis damage, inhibiting HSCs activation and collagen deposition, and remodeling gut microbiota homeostasis and metabolic imbalance. Notably, TSH attenuated hepatocyte ferroptosis in liver fibrosis and exhibited upregulation of the Nrf2-GPX4 signaling pathway. Furthermore, TSH could enrich the abundance of Parasutterella and Olsenellas, which may contribute to intestinal linoleic acid metabolism, thereby contributing to the reduction of liver fibrosis damage. Our study provides more effective and unreported evidence of TSH in anti-fibrosis activity.

Neutrophil elastase (Elane) is upregulated in metabolic-associated fatty liver disease (MAFLD) and has the capacity to promote disease progression. However, the mechanism by which Elane promotes MAFLD development remains unclear. Ferroptosis, which is an iron-dependent nonapoptotic form of cell death characterized by the iron-induced accumulation of lipid reactive oxygen species (ROS), has been recently considered as an important mechanism for the development of MAFLD. In this study, we used mice of Elane-knockout (Elane-KO) and wild-type (WT), and their primary mouse hepatocytes to establish MAFLD models in vivo and vitro for elucidating the role of Elane in ferroptosis of hepatocytes and MAFLD development. Elane-KO in vivo reduced high-fat diet (HFD) induced hepatic lipid peroxidation levels and the proportion of hepatocyte death, upregulated the expression of Nrf2 and Gpx4, and downregulated Keap1 expression. Treatment with recombinant Elane increased the lipid peroxidation level of hepatocytes, increased the ferroptosis rate of hepatocytes, upregulated the expression of Keap1, enhanced the ubiquitination of Nrf2, and downregulated the expression of Nrf2 and Gpx4 in an FFA-induced MAFLD in vitro model. However, primary hepatocytes from Elane-KO mice presented opposite changes. Furthermore, an in vitro experiment revealed that Elane enhanced the protein stability of Keap1 and thus increased Keap1 expression in hepatocytes by inhibiting the lysosomal degradation of the Keap1 protein. Finally, in vitro Co-IP experiments revealed that Elane increased the protein stability of Keap1 by weakening the binding between P62 and Keap1 and ultimately promoted hepatocyte Nrf2 ubiquitination and ferroptosis in MAFLD. In conclusion, our results suggested that Elane promoted hepatocyte ferroptosis in MAFLD through the P62-Keap1-Nrf2-Gpx4 axis. Elane promotes ferroptosis in hepatocytes from fatty livers. Elane reduces the binding of P62 to Keap1, thereby increasing Keap1 protein stability and subsequently inhibiting the Nrf2/Gpx4 pathway, ultimately leading to ferroptosis in hepatocytes.

Peste des petits ruminants virus (PPRV) is an important pathogen that seriously affects the productivity of small ruminants worldwide. Ferroptosis is a programmed cell death characterized by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS). Emerging evidence has demonstrated that mitochondria play diverse roles in the process of ferroptosis, but the interaction between mitochondria and ferroptosis during virus infection remains largely unknown. Here, we demonstrate that PPRV induces ferroptosis, including Fe2+ overload, accumulation of lipid peroxidation, and shrinkage of mitochondria. Importantly, mitochondria play a crucial role in the process of PPRV-induced ferroptosis characterized by decreased mitochondrial GPX4 and lipid peroxidation in mitochondria. Mechanistically, PPRV infection downregulates mitochondrial Lon protease-1 (LONP1) expression, an important multifaceted enzyme that is essential for maintaining mitochondrial homeostasis and function, which leads to mitochondrial GPX4 degradation through the Nrf2/Keap pathway and accumulation of ROS in mitochondria. More importantly, PPRV-induced ferroptosis is tightly associated with inflammatory responses and enhanced virus replication. Overall, this study is the first to show that LONP1-mediated ferroptosis is involved in the inflammatory responses during PPRV infection.

Peste des petits ruminants virus (PPRV) infection induces a transient but severe immunosuppression in the host, which threatens both small livestock and endangered susceptible wildlife populations in many countries. Despite extensive research, it is unknown whether PPRV causes ferroptosis and what the mechanism of regulation is. Our data provide the first direct evidence that the relationship between Lon protease-1 (LONP1)-mediated dysfunctional mitochondria and the consequent induction of ferroptosis is involved in PPRV-induced pathogenesis. Importantly, we demonstrate that PPRV infection induces ferroptosis via the LONP1-mediated GPX4 degradation and ROS accumulation in mitochondria, and PPRV-induced ferroptosis is tightly associated with inflammatory responses and enhanced virus replication levels. Taken together, our research has provided new insight into understanding the effect of ferroptosis on PPRV replication and pathogenesis and revealed a potential therapeutic target for antiviral intervention.

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

Alzheimer's disease (AD) is the most prevalent form of dementia, which continues to elude effective treatment despite decades of research and numerous clinical trials. While existing therapeutic strategies have primarily targeted neuropathological hallmarks such as amyloid plaques and tau tangles, they have failed to halt disease progression, leaving patients with limited options. This persistent failure reveals a critical gap in our understanding of AD and calls for a fresh perspective - one that goes beyond the traditional targets and dives deeper into the fundamental cellular processes that drive neurodegeneration. Recent advances in molecular biology underscore the significance of nuclear factor E2-related factor 2 (Nrf2), often termed the "guardian of redox homeostasis," in the pathophysiology of AD. Nrf2 orchestrates cellular responses to oxidative stress and neuroinflammation - two interlinked pathological features of AD. In the brains of AD patients, Nrf2 activity is diminished, weakening the brain's ability to counteract oxidative damage. Additionally, the BTB and CNC homology 1 (Bach1) protein, a transcriptional repressor of Nrf2, has emerged as a potential therapeutic target. Here, we review the current landscape of clinical trials in AD and identify the limitations of the conventional approaches. We then explore the prospects of a novel approach that combines Nrf2 activation with Bach1 inhibition to achieve a multipronged defense against oxidative stress, neuroinflammation, and other molecular culprits driving AD. This innovative strategy holds promise for synergistically modulating multiple neuroprotective pathways to advance AD treatment.

Sepsis is a syndrome of organ dysfunction caused by the invasion of pathogenic microorganisms. In clinical practice, patients with sepsis are prone to concurrent acute kidney injury, which has high morbidity and mortality rates. Thus, understanding the pathogenesis of sepsis-associated acute kidney injury is of significant clinical importance. Ferroptosis is an iron-dependent programmed cell death pathway, which is proved to play a critical role in the process of sepsis-associated acute kidney injury through various mechanisms. Epigenetic regulation modulates the content and function of nucleic acids and proteins within cells through various modifications. Its impact on ferroptosis has garnered increasing attention; however, the role of epigenetic regulation targeting ferroptosis in sepsis-associated acute kidney injury has not been fully elucidated. Growing evidence suggests that epigenetic regulation can modulate ferroptosis through complex pathway networks, thereby affecting the development and prognosis of sepsis-associated acute kidney injury. This paper summarizes the impact of ferroptosis on sepsis-associated acute kidney injury and the regulatory mechanisms of epigenetic regulation on ferroptosis, providing new insights for the targeted therapy of sepsis-associated acute kidney injury.

Protein tyrosine phosphatase mitochondrial 1 (PTPMT1), is a member of the protein tyrosine phosphatase superfamily localized on the mitochondrial inner membrane, and regulates the biosynthesis of cardiolipin. Given the important position of PTPMT1 in mitochondrial function and metabolism, pharmacological targeting of PTPMT1 is considered a promising manner in disease treatments. In this study, we mainly investigated the role of PTPMT1 in hepatocellular carcinoma (HCC) ferroptosis, a new type of cell death accompanied by significant iron accumulation and lipid peroxidation. Herein, the pharmacological inhibition of PTPMT1 was induced by alexidine dihydrochloride (AD, a dibiguanide compound). Human HCC cell lines with PTPMT1 knockout and PTPMT1 overexpression were established using CRISPR/Cas9 and lentiviral transduction methods, respectively. The position of PTPMT1 in regulating HCC ferroptosis was evaluated in vitro and in vivo. Our results indicated that pharmacological inhibition of PTPMT1, facilitated by AD treatment, heightens the susceptibility of HCC to cystine deprivation-ferroptosis, and AD treatment promoted the conversion from ferritin-bound Fe3+ to free Fe2+, which contributed to the labile iron pool in cytoplasm. Meanwhile, pharmacological inhibition of PTPMT1 also induced the formation of both swollen mitochondria and donut mitochondria, and enhanced the metabolism process form succinate to fumarate in mitochondrial tricarboxylic acid (TCA) cycle, which increased the sensitivity of HCC cells to cystine deprivation-induced ferroptosis. In total, our work reveals the close association of PTPMT1 with cysteine deprivation-induced ferroptosis, providing a novel insight into chemotherapy strategies against human HCC.

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

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

Cuproptosis is a newly identified form of cell death that relies on copper (Cu) ionophores to transport Cu into cancer cells. As a perennial herb, Patrinia scabiosaefolia Fisch (PS) has garnered significant attention owing to its analgesic, anti-inflammatory, antibacterial, and antitumor properties. Previous research has shown that the extract from PS (DEPS) can inhibit the growth of leukemia cell lines. However, the specific mechanism of its anti-leukemic effect has not been fully clarified. Therefore, this study was conducted to investigate the molecular mechanism of cuproptosis in the treatment of leukemia with DEPS. Our results demonstrated that DEPS up-regulated SLC31A1 and down-regulated ATP7B expression, which increased intracellular copper concentration, down-regulated FDX1, influenced the lipoylation of DLAT and DLD, and subsequently increased the expression of the stress protein HSP70 and the expression of PDHA1, inducing copper death in K562 cells. In addition, we investigated the toxicity of DEPS in vivo and demonstrated its low in vivo toxicity and adequate in vivo safety. In conclusion, our results suggest that DEPS may induce cuproptosis in cells, offering valuable insights for the future application of PS in leukemia treatment.

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.

Chronic kidney disease (CKD) has long represented a substantial global health challenge. Regrettably, current therapeutic interventions exhibit limited efficacy in halting the progression of CKD. Ferroptosis may play a crucial role in CKD, as indicated by substantial evidence. Dental pulp stem cell-derived exosomes (DPSC-Exos) possess advantages such as abundant sources and low immunogenicity, holding promising prospects in CKD treatment.

This study constructed a mouse CKD model to investigate the therapeutic effects of DPSC-Exos. First, we successfully extracted and identified DPSC-Exos. Then, mice were randomly divided into sham, PBS, CKD, and CKD+Exos groups. Our study determined the expression of ferroptosis-related pathway molecules Nrf2, GPX4, Keap1, and HO-1 in each group. Finally, we detected the expression levels of inflammatory factors, TNF-α, IL-1β, and IL-6, at the injury site.

Mice treated with DPSC-Exos showed increased expression of the ferroptosis inhibitory factor Nrf2 and its downstream regulatory factors GPX4 and HO-1, while the expression of Keap1 decreased. The expression of TNF-α, IL-1β, and IL-6 also decreased.

DPSC-Exos may help inhibit ferroptosis through the Keap1-Nrf2/GPX4 pathway and reduce the inflammatory response at the injury site, revealing their potential therapeutic effects on CKD.

The magnetic properties of substances directly determine their response to an externally applied magnetic field, which are closely associated with magnetoreception, magnetic resonance imaging (MRI), and magnetic bioeffects. However, people's understanding of the magnetic properties of living organisms remains limited. In this study, we utilized NRF2 (nuclear factor erythroid 2-related factor 2) deficient mice to investigate the contribution of redox (oxidation-reduction) homeostasis, in which the key process is the transfer of electron, a direct target of magnetic field and origin of paramagnetism. Our results show that the NRF2-/- mice exhibit significantly altered systemic redox state, accompanied by increased magnetic susceptibility, particularly in the liver and spleen. Further analyses reveal that the levels of paramagnetic reactive oxygen species (ROS) in these tissues are markedly elevated compared to wild-type mice. Moreover, the concentrations of Fe2+ and Fe3+ are significantly elevated in NRF2-/- mice, which are directly correlated with the increased magnetic susceptibility. The disrupted redox balance in NRF2-/- mice not only exacerbates oxidative stress and iron deposition, but also induces impairment to the liver and spleen. The findings highlight the combined effects of ROS and iron metabolism in driving magnetic susceptibility changes, providing valuable theoretical insights for further research into magnetic bioeffects and organ-specific sensitivity to magnetic fields.

Ferroptosis is a form of regulating cell death, and iron accumulation in the brain after acute ischemic stroke (AIS) is associated with the triggering of iron metabolism. Nuclear factor erythroid 2-related factor 2 (Nrf2), one of the most critical antioxidant transcription factors in cells, is closely associated with ferroptosis and oxidative stress.In the present study, we explore the intrinsic mechanisms by which Nrf2 exerts neuroprotective effects against AIS-induced ferroptosis.In vivo experiments, we explored the protective effects of AIS induced by middle cerebral artery occlusion (MCAO) and its mechanisms by using intraperitoneal injections of ferrostatin-1 (Fer-1, an inhibitor of ferroptosis), Oltipraz (an agonist of Nrf2) and ML385 (an inhibitor of Nrf2) in wild-type (WT) mice, as well as using Nrf2-/- mice. In vitro experiments, we investigated the mechanism of action of Nrf2 on the establishment of a ferroptosis cell model induced by Erastin by overexpressing or silencing Nrf2 expression using shRNA in SH-SY5Y cells.Ferroptosis played an important role in AIS, and Fer-1 inhibited iron accumulation and alleviated neuronal damage caused by AIS.Oltipraz attenuated AIS-induced neuronal damage and cerebral infarction by increasing cortical blood flow (CBF). Additionally, Oltipraz protected against AIS-induced ferroptosis by reducing oxidative stress and iron overload. Meanwhile, in Oltipraz-treated AIS mice, Nrf2, solute carrier family 7 member 11 (SLC7A11/xCT), and glutathione peroxidase 4 (GPX4) were upregulated. Conversely, ML385 decreased CBF and exacerbated IS-induced neuronal damage. Furthermore, both ML385 treatment and Nrf2 knockout mice exacerbated oxidative stress injury and iron overload and downregulated the expression of both xCT and GPX4. Consistent with the in vivo results, Nrf2 conferred ferroptosis resistance in vitro upon exposure to compounds that induce ferroptosis, by modulating the xCT/GPX4 pathway.The present study confirmed that Nrf2 could attenuate AIS-induced neuronal ferroptosis and oxidative stress by regulating xCT/GPX4.

Ruminal dysbiosis-induced liver injury is prevalent in dairy cows, yet its underlying mechanisms remain incompletely understood. Ferroptosis, a newly identified form of programmed cell death distinct from apoptosis and necrosis, has been implicated in various liver diseases by emerging studies. In the present study, lipopolysaccharide (LPS) and γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) were employed to establish in vitro and in vivo models of liver injury using bovine hepatocytes and mice, respectively. It was observed that noncytotoxic iE-DAP alone did not influence lipid peroxidation or GPX4, but exacerbated LPS-induced ferroptosis and hepatocyte injury. Notably, co-treatment with LPS and iE-DAP (LPS/iE-DAP)-induced hepatocyte injury was mitigated by intervention with the ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistically, the activated IL-6/STAT3 signaling pathway was found to mediate LPS/iE-DAP-induced ferroptosis. Suppression of IL-6/STAT3, either through IL6 and STAT3 knockdown or pharmacological intervention, reduced Fe2+ accumulation and alleviated ferroptotic cell death. Further investigations identified that IL-6/STAT3 signaling enhanced ferritinophagy and impaired iron export. Either disrupting ferritinophagy by knocking down NCOA4 or restoring iron export via HAMP knockdown relieved intracellular iron overload and inhibited ferroptosis. Specifically, LPS/iE-DAP treatment increased the interaction between hepcidin and ferroportin, promoting ferroportin ubiquitination and degradation, thereby blocking iron efflux. Furthermore, we provided several evidence to prove that quercetin pretreatment alleviated LPS/iE-DAP-induced ferroptosis and liver injury by decreasing hepatic iron accumulation via targeting the IL-6/STAT3 signaling in vitro and in vivo, effects reversed by the addition of recombinant bovine IL-6. Based on these findings, we concluded that LPS/iE-DAP-induced liver injury by triggering ferroptosis through regulating IL-6/STAT3/ferritinophagy-dependent iron release and IL-6/STAT3/hepcidin/ferroportin-dependent iron export, while quercetin could alleviate this liver injury by inhibiting ferroptosis via IL-6/STAT3 signaling pathway. This study provides novel insights into the mechanisms whereby ruminal dysbiosis induces liver injury and presents a prospective solution for ruminal dysbiosis-induced liver injury.

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.

Cardiovascular disease (CVD) is a leading cause of human mortality worldwide, with patients often at high risk of heart failure (HF) in myocardial infarction (MI), a common form of CVD that results in cardiomyocyte death and myocardial necrosis due to inadequate myocardial perfusion. As terminally differentiated cells, cardiomyocytes possess a severely limited capacity for regeneration, and an excess of dead cardiomyocytes will further stress surviving cells, potentially exacerbating to more extensive heart disease. The article focuses on the relationship between programmed cell death (PCD) of cardiomyocytes, including different forms of apoptosis, necrosis, and autophagy, and MI, as well as the potential application of these mechanisms in the treatment of MI. By gaining a deeper understanding of the mechanisms of cardiomyocyte death, it aims to provide new insights into the prevention and treatment of MI.

Nootkatone (NK), a sesquiterpene naturally derived from citrus species, was investigated for its protective effect against UVB-induced damage in HaCaT cells and its underlying mechanisms. NK effectively suppressed UVB-mediated cell death and significantly modulated expression of skin hydration genes; NK (100 μM) increased mRNA levels of collagen-1 and HAS by 44.6 and 34.7%, respectively, while downregulating HYAL by 46.8%. NK also reduced MMP1/2 expression, key matrix metalloproteinases, but enhanced mRNA levels of skin barrier factors, Filaggrin, Loricrin, and Involucrin by up to 45%. Additionally, NK lowered UVB-induced ROS production and elevated antioxidant levels (NRF2, HO-1, catalase, SOD1, and Gpx), and decrease the protein levels of xenobiotic factors, AhR and CYP1A1. These findings suggest that NK protects skin integrity against UVB-induced photoaging through the modulation of NRF2-HO-1 and AhR-CYP1A1 signaling pathways. NK shows promise as a functional agent, either edible or topical, for protecting against UVB-induced skin damage.

The online version contains supplementary material available at 10.1007/s10068-024-01791-x.

Spinal cord injury (SCI) is a serious central nervous system injury that often causes sensory and motor dysfunction in patients. Diabetes seriously destroys the blood spinal cord barrier (BSCB) and aggravates SCI. Ferroptosis is a new type of programmed cell death. The role of ferroptosis in diabetes-medicated BSCB destruction has not been clearly elucidated. Here, we built a type 1 diabetes (T1D) combined with SCI rat model and confirmed that hyperglycemia exacerbates SCI-mediated BSCB destruction. Pathological mechanism demonstrated that except for apoptosis, the excessive ferroptosis is another caused factor for endothelial cells (ECs) loss under hyperglycemic condition. More importantly, ferrostatin-1(a ferroptosis inhibitor) treatment significantly inhibited the ferroptosis of ECs, and promoted the BSCB repair in T1D combined with SCI rat. The mechanism study further revealed that hyperglycemia not only induces the elevated reactive oxygen species (ROS) via activating RAGE, but also suppresses the xCT expression in system Xc- in ECs, which decreases GPX4 expression and induces ferroptosis. Additionally, hyperglycemia also accelerated the transfer of iron ions from serum to spinal cord after SCI. In summary, our results suggest that the excessive ferroptosis of ECs is essential for the severe BSCB destruction in T1D combined with spinal cord injury rat.

Abdominal aortic aneurysm (AAA) is a life-threatening disease featuring extensive membrane destruction in the vascular wall, which is closely associated with the phenotypic switching of vascular smooth muscle cells (VSMC). A thorough understanding of the changes in regulatory factors during the pathogenesis of VSMC phenotypic switching is essential for medical treatments in AAA. NRF2 was deemed to hold a pivotal position in developing AAA, especially as it can regulate VSMC phenotypic switching. In this study, we found that berberine prevents the formation of AAA by regulating the phenotypic switching of VSMC, which was well validated in both in vitro and in vivo functional experiments. Mechanically, we found that berberine regulates VSMC phenotypic switching by promoting the expression of downstream VSMC contraction genes through the deubiquitination of Keap1, in which the deubiquitinating enzyme USP15 plays an important mediating role in this process.

Dysregulation in placental trophoblast cells frequently results in oxidative stress, culminating in pregnancy-related complications. While iron is essential for fetal development, cellular ferroptosis due to elevated iron levels might mediate the emergence of preeclampsia (PE), presenting significant risks during gestation. We found abnormally activated oxidative stress and increased iron concentration in the placental tissues of PE patients. Subsequently, we treated placental trophoblasts with hydrogen peroxide and RSL3 to induce oxidative stress and ferroptosis models. The results revealed that SIRT6 overexpression activates the Nrf2/HO-1 pathway, restores the oxidative imbalance of the cells, and protects the cells from ferroptosis. Meanwhile, activation of the Nrf2/HO-1 pathway alone showed similar results. Thus, we posit that SIRT6, via the Nrf2/HO-1 pathway, alleviates cellular oxidative stress and diminishes ferroptosis, offering a novel therapeutic avenue for PE.

Brain tumors are complex, heterogeneous malignancies, often associated with significant morbidity and mortality. Emerging evidence suggests the important role of metabolic syndrome, such as that observed in diabetes mellitus, in the progression of brain tumors. Several studies indicated that hyperglycemia, insulin resistance, oxidative stress, and altered adipokine profiles influence tumor growth, proliferation, and treatment resistance. Intriguingly, antidiabetic drugs (e.g., metformin, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and thiazolidinediones) have shown promise as adjunctive or repurposed agents in managing brain tumors. Metformin can impair tumor cell proliferation, enhance treatment sensitivity, and modify the tumor microenvironment by activating AMP-activated protein kinase (AMPK) and inhibiting mammalian target of rapamycin (mTOR) signaling pathways. DPP-4 inhibitors and GLP-1 receptor agonists can target both metabolic and inflammatory aspects of brain tumors, while thiazolidinediones may induce apoptosis in tumor cells and synergize with other therapeutics. Consequently, further studies and clinical trials are needed to confirm the efficacy, safety, and utility of metabolic interventions in treating brain tumors. Here, we review the evidence for the metabolic interconnections between metabolic diseases and brain tumors and multiple actions of anti-diabetes drugs in brain tumors.

Ferroptosis is a type of cell death marked by iron-dependent lipid peroxide accumulation. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the catabolism of tryptophan through kynurenine pathway, participates in the development of multiple tumor types. However, the role of IDO1 in tumor ferroptosis is unclear. In this study, we identified IDO1 as a key regulator of ferroptosis in lung cancer. With Erastin-treated lung cancer cells, we found that IDO1 inhibited ferroptosis, reduced the generation of lipid peroxide and ROS. Mechanistically, IDO1 promoted the expression of nuclear factor erythroid 2-related factor 2 (NRF2) through activating aryl hydrocarbon receptor (AhR) pathway. IDO1 up-regulated the expression of solute carrier family 7 member 11 (SLC7A11) and the activity of pentose phosphate pathway (PPP) via AhR-NRF2 axis, promoted the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby inhibiting ferroptosis. Moreover, combined treatment with IDO1 inhibitor and Erastin inhibited tumor growth, down-regulated SLC7A11 expression and PPP activity, promoted tumor ferroptosis in lung cancer-bearing mice. In conclusion, this study revealed the function of IDO1 in lung cancer ferroptosis and provided a new strategy for lung cancer therapy.

Acute ischemic stroke poses major challenges due to high disability and mortality rates. Ferroptosis, a form of regulated cell death triggered by iron-induced oxidative stress, plays a key role in stroke injury. Despite its long history in stroke treatment, the mechanism of Buyang Huanwu Decoction (BHD) in ferroptosis remains unclear.

Network pharmacology predicted BHD's active components and pathways, while Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) confirmed its main ingredients. Middle Cerebral Artery Occlusion (MCAO) was induced in C57 mice, with neurological deficits and infarct size assessed by Longa scoring and TTC staining. Histopathological and ultrastructural changes were assessed by staining and electron microscopy, and biochemical markers (MDA, GSH, SOD, Fe²+) measured by kits. Western blotting and qPCR analyzed ferroptosis-related proteins, Nrf2 localization, and gene expression. In vitro, HT22 cells viability and ROS levels were assessed under Oxygen-Glucose Deprivation/Reoxygenation (OGD/R) conditions. Protein expression, Nrf2 interactions, and nuclear translocation were also investigated.

Network pharmacology showed BHD targets key pathways in cerebral infarction, including ferroptosis and antioxidant pathways. BHD improved neurological function and reduced the infarct size in MCAO mice by 10% - 50%, and also significantly decreased the levels of oxidative stress markers (MDA, Fe2+) while increasing the activities of antioxidants (GSH, SOD). Histopathological and ultrastructural analyses demonstrated reduced neuronal damage and improved mitochondrial structure. Western blot and qPCR indicated upregulation of GPX4 and Nrf2, downregulation of Keap1, and Nrf2 nuclear translocation. In vitro, BHD enhanced HT22 cell viability and reduced ROS under stress. Protein analysis confirmed increased Nrf2, GPX4, and HO-1, with decreased Keap1 and enhanced Nrf2 nuclear translocation. Nrf2 inhibitor experiments confirmed BHD's effects are Nrf2-mediated.

In pre-clinical studies, BHD exerts neuroprotective effects in ischemic stroke by inhibiting ferroptosis through the Nrf2/GPX4 pathway.

Cardio-cerebrovascular diseases (CCVDs) are the leading cause of global mortality, yet effective treatment options remain limited. Ferroptosis, a novel form of regulated cell death, has emerged as a critical player in various CCVDs, including atherosclerosis, myocardial infarction, ischemia-reperfusion injury, cardiomyopathy, and ischemic/hemorrhagic strokes. This review highlights the core mechanisms of ferroptosis, its pathological implications in CCVDs, and the therapeutic potential of targeting this process. Additionally, it explores the role of Chinese herbal medicines (CHMs) in mitigating ferroptosis, offering novel therapeutic strategies for CCVDs management. Ferroptosis is regulated by several key pathways. The GPX4-GSH-System Xc- axis is central to ferroptosis execution, involving GPX4 using GSH to neutralize lipid peroxides, with system Xc- being crucial for GSH synthesis. The NAD(P)H/FSP1/CoQ10 axis involves FSP1 regenerating CoQ10 via NAD(P)H, inhibiting lipid peroxidation independently of GPX4. Lipid peroxidation, driven by PUFAs and enzymes like ACSL4 and LPCAT3, and iron metabolism, regulated by proteins like TfR1 and ferritin, are also crucial for ferroptosis. Inhibiting ferroptosis shows promise in managing CCVDs. In atherosclerosis, ferroptosis inhibitors reduce iron accumulation and lipid peroxidation. In myocardial infarction, inhibitors protect cardiomyocytes by preserving GPX4 and SLC7A11 levels. In ischemia-reperfusion injury, targeting ferroptosis reduces myocardial and cerebral damage. In diabetic cardiomyopathy, Nrf2 activators alleviate oxidative stress and iron metabolism irregularities. CHMs offer natural compounds that mitigate ferroptosis. They possess antioxidant properties, chelate iron, and modulate signaling pathways like Nrf2 and AMPK. For example, Salvia miltiorrhiza and Astragalus membranaceus reduce oxidative stress, while some CHMs chelate iron, reducing its availability for ferroptosis. In conclusion, ferroptosis plays a pivotal role in CCVDs, and targeting it offers novel therapeutic avenues. CHMs show promise in reducing ferroptosis and improving patient outcomes. Future research should explore combination therapies and further elucidate the molecular interactions in ferroptosis.