In recent years, the mechanisms of ferroptosis and cuproptosis, two novel modes of cell death, have been elucidated and have attracted much attention. Ferroptosis is dependent on the metabolic disruption of iron ions and lipid peroxidation, whereas cuproptosis is closely related to intracellular accumulation of copper ions, aggregation of lipoylated proteins and damage to FeS cluster proteins. In particular, oxidative stress plays an important role in both types of cell death. During ferroptosis, the central role of oxidative stress is reflected in the overproduction of reactive oxygen species (ROS) and lipid peroxidation of the cell membrane. Recent studies have revealed that ROS can propagate over long distances across cells in the form of trigger waves, triggering large-scale ferroptosis. In embryonic development, different regional redox states can limit the long-distance propagation of ferroptosis waves, which is critical for muscle remodeling and tissue formation during development. In cuproptosis, processes such as copper ions accumulation, tricarboxylic acid (TCA) cycle blockade, and reduced level of FeS cluster proteins are closely associated with oxidative stress. In addition, there is a close link between oxidative stress and death induced by other metal ions (Ca2+, Zn2+, etc.). In this paper, we review the role of oxidative stress in ferroptosis and cuproptosis and the related research progress to provide new ideas for understanding the mechanism of cell death and the occurrence and treatment of related diseases.

Pancreatic adenocarcinoma (PDAC) is one of the cancers with a very poor prognosis for its highly invasive and metastatic ability. Epithelial-mesenchymal transition (EMT) is critical for metastasis and invasion of PDAC cells, in which the expression of epithelial genes, such as E-cadherin (CDH1), decreases and that of mesenchymal genes increases. Transcription factor BTB and CNC homology 1 (BACH1) promotes EMT of PDAC cells in part by indirectly suppressing the expression of CDH1. However, the mechanism behind this is not yet clear. Considering recent reports on a link between intracellular iron and CDH1 expression in cancer cells, we examined whether BACH1 represses CDH1 expression by regulating ferritin gene. When AsPC-1 PDAC cells were treated with the iron chelator deferasirox (DFX), CDH1 expression was increased. While BACH1 knockdown resulted in increased CDH1 expression, combined knockdown of BACH1 and ferritin heavy chain gene (FTH1) reversed CDH1 expression. Tank-binding kinase 1 (TBK1), an upstream regulator of BACH1, was necessary to maintain EMT gene expression patterns in AsPC-1 cells. TBK1 was redundant with BACH1 to maintain VIM expression in SW1990 PDAC cells, suggesting its BACH1-independent role in EMT. Therefore, the regulation of CDH1 and EMT by BACH1 involves FTH1 and intracellular iron as mediators and TBK1 as an upstream and parallel regulator.

The cardiotoxicity of Adriamycin(ADR) limits its clinical application, and its molecular mechanism is not very clear. At present, Dexrazoxane (DXZ) is the only approved drug to prevent ADR-induced cardiotoxicity (DIC), but it also has serious adverse reactions. Therefore, it is a key scientific challenge to find a drug with strong myocardial protection, few adverse reactions and no effect on the anti-tumor effect of ADR. In this study, we established the DIC model in rats. Cardiomyocyte hypertrophy and myocardial fibrosis increased significantly, and MDA and LDH increased significantly in serum. Dexmedetomidine (DEX) is a carbohydrate with multiple biological activities that can significantly improve the above DIC process. Echocardiography confirmed that DEX could reverse the changes of ESV, EDV, EF and FS induced by ADR. In vitro, experiments confirmed that DEX reversed the upregulation of ANP, BNP, MHC and Collagen III protein levels induced by ADR. DEX improves DIC by inhibiting ferroptosis. Erastin, a ferroptosis agonist, confirmed that DEX improved DIC by inhibiting ferroptosis. Mechanically, DEX increases the expression of Nrf2 in the nucleus through the Akt/Gsk3β signalling axis, thereby regulating ferroptosis in cardiomyocytes. In addition, DEX can improve DIC while not affecting the anti-tumor effect of ADR.

Suppressing bone mesenchymal stem cell (BMSC) ferroptosis is expected to optimize BMSCs-based therapy for intervertebral disc degeneration (IVDD). Our previous study revealed that Prominin-2 could protect against ferroptosis by decreasing cellular Fe2+ content and inhibiting transcription regulator protein BACH1 (BACH1) expression. In this study we probed the molecular mechanisms underlying the Prominin-2/BACH1 pathway in BMSC ferroptosis. Using an array of in vitro and in vivo experiments we found that heat shock factor protein 1 (HSF1) activates PROM2 (encoding protein Prominin-2) transcription and elevated Prominin-2 expression. Furthermore, we showed that Prominin-2 attenuates ferroptosis induced by tert-butyl hydroperoxide (TBHP) through promoting BACH1 ubiquitination and degradation. Inhibition of BACH1 expression reversed TBHP-stimulated down expression of glutaminase kidney isoform, mitochondrial (GLS), which plays a crucial role in protecting BMSCs against ferroptosis. Targeting the Prominin-2/BACH1 axis has also been shown to improve BMSC survival post-transplantation and mitigate IVDD progression by inhibiting ferroptosis. Our results support a new mechanistic insight into the regulation of the Prominin-2/BACH1/GLS pathway in BMSC ferroptosis. These finding could lead to potential therapeutic targets to improve the survival of engrafted BMSCs under oxidative stress circumstances.

There is a positive causality between coffee consumption and osteoarthritis (OA); however, whether gut microbiota is involved needs to be discussed. Here, we observed that in caffeine consumers, fecal Prevotella copri abundance was positively correlated with subchondral bone mass, serum caffeine concentration was negatively correlated with bone mass, and fecal P. copri was negatively correlated with serum caffeine. In the OA model, caffeine intake aggravated articular cartilage destruction, bone mass loss, and intestinal barrier damage; on the contrary, paraxanthine intake reversed the above lesions. Importantly, after the intestinal P. copri supplement, caffeine-induced lesions in OA mice were effectively alleviated. Mechanically, P. copri has the potential to metabolize caffeine into paraxanthine, and this effect could alleviate the ferroptosis of osteoblast in the OA model. This study screened out that P. copri, an endogenous bacteria, has the ability to metabolize caffeine and revealed its effects on OA progression.IMPORTANCEThere is positive causality between coffee consumption and osteoarthritis (OA). Caffeine exposure is responsible for the reduction of bone mass and restrained osteoblast function. Prevotella copri abundance is exhausted in gut and positively correlated with subchondral bone mass in coffee consumption patients with OA. Supplement of intestinal P. copri alleviates caffeine-induced subchondral bone loss. P. copri has the potential to metabolize caffeine into paraxanthine, and this effect alleviates ferroptosis of osteoblast. Our study illustrated that intestinal P. copri possibly serves as a novel promising treatment for coffee consumers with OA.

To increase livestock productivity and improve economic efficiency, farms tend to focus on the growth rate of livestock and poultry. This strategy can result in a reduced resistance to reactive oxidative stress (ROS) and heat stress. Selenomethionine (SeMet) and allicin have antioxidant properties, but their excessive intake can lead to toxicity. Co-administration improves antioxidant protection and reduces side-effects but also reduces the cost of administration. We undertook a study to elucidate the antioxidant effect of glutathione peroxidase (GPX) 4 in SeMet and allicin. The synergistic antioxidant effect, attenuation of endoplasmic reticulum stress (ERS), enhancement of expression of tight-junction proteins, and inhibition of apoptosis, ferroptosis, inflammatory responses of SeMet and allicin were attenuated significantly after inhibition of GPX4 according to western blotting (P < 0.05). These results indicated that activation of the GPX4 pathway was the key to the synergistic maintenance of barrier function, attenuation of ERS, as well as inhibition of apoptosis, ferroptosis, and inflammatory responses by SeMet and allicin. SeMet and allicin could protect the intestinal barrier from oxidative damage by synergistically activating the GPX4 pathway, increasing antioxidant capacity, and improving growth performance. In conclusion, SeMet and allicin could be used as a new drug combination to alleviate diseases associated with intestinal ROS and aid in the development of new antioxidant feed additives.

In murine models of visceral leishmaniasis (VL), the parasitization of resident Kupffer cells (resKCs) drives early Leishmania infantum growth in the liver, leading to granuloma formation and subsequent parasite control. Using the chronic VL model, we demonstrate that polyclonal resKCs redistributed to form granulomas outside the sinusoids, creating an open sinusoidal niche that was gradually repopulated by monocyte-derived KCs (moKCs) acquiring a tissue specific, homeostatic profile. Early-stage granulomas predominantly consisted of CLEC4F+KCs. In contrast, late-stage granulomas led to remodeling of the sinusoidal network and contained monocyte-derived macrophages (momacs) along with KCs that downregulated CLEC4F, with both populations expressing iNOS and pro-inflammatory chemokines. During late-stage infection, parasites were largely confined to CLEC4F-KCs. Reduced monocyte recruitment and increased resKCs proliferation in infected Ccr2-/- mice impaired parasite control. These findings show that the ontogenic heterogeneity of granuloma macrophages is closely linked to granuloma maturation and the development of hepatic immunity in VL.

Respiratory infectious diseases, particularly those caused by respiratory viruses, have the potential to lead to global pandemics, thereby posing significant threats to public and human health. Historically, the primary treatment for respiratory bacterial infections has been antibiotic therapy, while severe cases of respiratory viral infections have predominantly been managed by controlling inflammatory cytokine storms. Ferroptosis is a novel form of programmed cell death that is distinct from apoptosis and autophagy. In recent years, Recent studies have demonstrated that ferroptosis plays a significant regulatory role in various respiratory infectious diseases, indicating that targeting ferroptosis may represent a novel approach for the treatment of these conditions. This article summarized the toxic mechanisms underlying ferroptosis, its relationship with respiratory infectious diseases, the mechanisms of action, and current treatment strategies. Particular attentions were given to the interplay between ferroptosis and Mycobacterium tuberculosis, Epstein-Barr virus, severe acute respiratory syndrome coronavirus-2, Pseudomonas aeruginosa, dengue virus, influenza virus and herpes simplex virus type1infection. A deeper understanding of the regulatory mechanisms of ferroptosis in respiratory infections will not only advance our knowledge of infection-related pathophysiology but also provide a theoretical foundation for the development of novel therapeutic strategies. Targeting ferroptosis pathways represents a promising therapeutic approach for respiratory infections, with significant clinical and translational implications.

Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates defenses against oxidants and thiol-reactive electrophiles. It is controlled at the protein stability level by several E3 ubiquitin ligases (CRL3Keap1, CRL4DCAF11, SCFβ-TrCP, and Hrd1). CRL3Keap1 is of the greatest importance because it constitutively targets Nrf2 for proteasomal degradation under homeostatic conditions but is prevented from doing so by oxidative stressors. Repression of Nrf2 by CRL3Keap1 is attenuated by SQSTM1/p62, and this is reinforced by phosphorylation of SQSTM1/p62. Repression by SCFβ-TrCP requires phosphorylation of Nrf2 by GSK3, the activity of which is inhibited by PKB/Akt and other kinases. We discuss how Nrf2 activity is controlled by the ubiquitin ligases under different circumstances. We also describe endogenous signaling molecules that inactivate CRL3Keap1 to alleviate stress and restore homeostasis.

BTB domain and CNC homolog 1 (BACH1) belongs to the family of basic leucine zipper proteins and is expressed in most mammalian tissues. It can regulate its own expression and play a role in transcriptionally activating or inhibiting downstream target genes. It has a crucial role in various biological processes, such as oxidative stress, cell cycle, heme homeostasis, and immune regulation. Recent research highlights BACH1's significant regulatory roles in a series of conditions, including stem cell pluripotency maintenance and differentiation, growth, senescence, and apoptosis. BACH1 is closely associated with cardiovascular diseases and contributes to angiogenesis, atherosclerosis, restenosis, pathological cardiac hypertrophy, myocardial infarction, and ischemia/reperfusion (I/R) injury. BACH1 promotes tumor cell proliferation and metastasis by altering tumor metabolism and the epithelial-mesenchymal transition phenotype. Moreover, BACH1 appears to show an adverse role in diseases such as neurodegenerative diseases, gastrointestinal disorders, leukemia, pulmonary fibrosis, and skin diseases. Inhibiting BACH1 may be beneficial for treating these diseases. This review summarizes the role of BACH1 and its regulatory mechanism in different cell types and diseases, proposing that precise targeted intervention of BACH1 may provide new strategies for human disease prevention and treatment.

Salsolinol (SAL), i.e.1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroiso-quinoline, is a dopamine metabolite and endogenous neurotoxin that is toxic to dopaminergic neurons, and is involved in the genesis of Parkinson's disease (PD). However, the machinery underlying SAL induces neurotoxicity in PD are still being elucidated. In the present study, we first used RNA sequencing (RNAseq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to detect differentially expressed genes in SAL-treated SH-SY5Y cells. We found that ferroptosis-related pathway was enriched by SAL, which was validated by in vitro and in vivo SAL models. SAL inducing ferroptosis through downregulating SLC7A11/GPX4 in SH-SY5Y cells, which neurotoxic effect was reversed by ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (Fer-1). Acteoside, a phenylethanoid glycoside of plant origin with neuroprotective effect, attenuates SAL-induced neurotoxicity by inhibiting ferroptosis in in vitro and in vivo PD models through upregulating SLC7A11/GPX4. Mechanistically, acteoside activates Nrf2. Nrf2 inhibitor ML385 abolished acteoside-mediated increased SLC7A11/GPX4 and neuroprotection against SAL in SH-SY5Y cells. Meanwhile, the PI3K inhibitor LY294002 suppressed the acteoside-induced Nrf2 expression and ensued decreased expression of SLC7A11/GPX4 in SAL-treated SH-SY5Y cells. Taken together, these results demonstrate that salsolinol-induced PD through inducing ferroptosis via downregulating SLC7A11/GPX4. Acteoside attenuates SAL-induced PD through inhibiting ferroptosis via activating PI3K/Akt-dependant Nrf2. The present study revealed a novel molecular mechanisms underlining SAL-induced neurotoxicity via induction of ferroptosis in PD, and uncovered a new pharmacological effect against PD through inhibiting ferroptosis. This study highlights SAL-induced ferroptosis -dependent neurotoxicity as a potential therapeutic target in PD.

Targeted temperature management (TTM) is a vital intervention for cardiac arrest survivors to mitigate post-resuscitation myocardial dysfunction (PRMD). However, the optimal temperature for TTM remains a topic of debate. This study investigates the effects of TTM at different temperatures and explores the underlying mechanisms using in vivo and in vitro models of myocardial ischemia/reperfusion (I/R) injury following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). We found that TTM at 33 °C significantly improved post-resuscitation hemodynamics and myocardial function, reducing both myocardial and mitochondrial damage in the rat model of CA/CPR. Additionally, Deferoxamin (DFO), as an iron chelating agent, also demonstrated protective effects against PRMD. Both in vitro and in vivo experiments confirmed that hypothermia at 33 °C and DFO mitigated mitochondrial damage, oxidative stress, lipid peroxidation, and iron overload, while suppressing ferritinophagy and ferroptosis. Furthermore, TTM at 33 °C and DFO facilitated the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), with Nrf2 activation leading to inhibited ferritinophagy and enhanced iron export. Our findings indicate that TTM at 33° C, as opposed to 36° C, significantly alleviates PRMD and reduced myocardial damage by inhibiting ferroptosis. Theses protective effects are associated with Nrf2 activation and modulation of iron homeostasis. Moreover, DFO not only suppressed ferroptosis through its iron chelation properties but also by activating the Nrf2 axis.

The ever-increasing chemoresistance of osteosarcoma (OS) has been observed in the recent decades, impeding OS therapeutic improvement and posing an urgency to exploit to the alternative and/or supplementary therapies for the optimization of OS chemotherapeutic regimen. Ferroptosis, a regulated cell death, has been identified as a natural anticancer mechanism as well as a synergist for chemotherapeutics in various cancers. Herein, we affirmed the tumor-suppressing properties of eriodictyol and illustrated that its antitumor effects might ascribe to the ferroptosis-inducing activity, in which eriodictyol could bind with BACH1 to repress the transcription and translation of GPX4 and eventually result in the GPX4-related ferroptosis. Further investigation found that eriodictyol could exhibit a synergistic effect with cisplatin, facilitating the antitumor effects of cisplatin. Lastly, through utilizing hollow mesoporous prussian blue nanocubes loaded with eriodictyol and cisplatin, we formed the ferroptosis-synergistic nanocomplexes to facilitate OS cells ferroptosis and cisplatin sensitivity. Through direct catalytic oxidation of unsaturated lipids, exogenous iron delivery, GSH exhaustion, and GPX4 transcriptional inhibition, this ferroptosis-synergistic nanocomplex could excellently enhance OS cells ferroptosis in both vitro and vivo, with no obvious organ injury observed. Therefore, our ferroptosis-synergistic nanocomplex may represent a promising alternative therapeutic strategy for OS patients.

Traumatic brain injury (TBI) is one of the leading causes of disability and mortality, which was classified as low-altitude TBI and high-altitude TBI. A large amount of literature shows that high-altitude TBI is associated with more severe neurological impairments and higher mortality rates compared to low-altitude TBI, due to the special environment of high-altitude hypoxia. However, the role of high-altitude hypoxia in the pathogenesis of TBI remains unclear. In order to deeply investigate this scientific issue, we constructed a high-altitude hypoxic TBI model at different altitudes and used animal behavioral assessments (Modified neurological severity score, rotarod test, elevated plus maze test) as well as histopathological analyses (brain gross specimens, brain water content, Evans blue content, hypoxia inducible factor-1α, Hematoxylin-Eosin staining and ROS detection) to reveal its underlying principles and characteristics. We found that with higher altitude, TBI-induced neurological deficits were more severe and the associated histopathological changes were more significant. Single-nuclear RNA sequencing was subsequently employed to further reveal differential gene expression profiles in high-altitude TBI. We found a significant increase in ferroptosis of astrocytes in cases of high-altitude TBI compared to those at low-altitude TBI. Analyzing transcription factors in depth, we found that Bach1 plays a crucial role in regulating key molecules that induce ferroptosis in astrocytes following high-altitude TBI. Down-regulation of Bach1 can effectively alleviate high-altitude TBI-induced neurological deficits and histopathological changes in mice. In conclusion, high-altitude hypoxia may significantly enhance the ferroptosis of astrocytes and aggravate TBI by up-regulating Bach1 expression. Our study provides a theoretical foundation for further understanding of the mechanism of high-altitude hypoxic TBI and targeted intervention therapy.

Cytotoxic effects of cigarette smoke are thought to be causes of cigarette smoking-related diseases such as respiratory infection, chronic obstructive pulmonary disease, and atherosclerosis. Unsaturated carbonyl compounds are major cytotoxic factors in the gas phase of cigarette smoke. Cell death induced by unsaturated carbonyl compounds in cigarette smoke is PKC-dependent ferroptosis. Although the cell sensitivity to unsaturated carbonyl compounds varies by cell types, the molecular mechanisms underlying this sensitivity remain unclear. In this study, we have examined the factors involved in determining sensitivity to unsaturated carbonyl compounds. We found that two mouse macrophage cell lines exhibited different sensitivities; J774.1 macrophages were sensitive to unsaturated carbonyl compounds, whereas RAW264.7 macrophages were resistant. Glutathione synthesis inhibitor increased the sensitivity of RAW264.7 macrophages to unsaturated carbonyl compounds. Quantitative RT-PCR revealed that the expression level of the cystine transporter SLC7A11 was higher in RAW264.7 macrophages than in J774.1 macrophages. Inhibition of SLC7A11 activity increased sensitivity to unsaturated carbonyl compounds, while overexpression of SLC7A11 enhances resistance to these compounds. The current results suggest that the SLC7A11 level is a key factor in determining the macrophage sensitivity to unsaturated carbonyl compounds.

Neuronal protection is a well-established method of acute ischemic stroke (AIS) treatment. The pharmacodynamic effect of Piceatannol-3'-O-β-D-glucopyranoside (Chinese name: Hartigan, QZZG) on AIS has been reported, but the molecular mechanism of this effect remains unknown.

The purpose of this study is to elucidate the pharmacodynamic effects and mechanisms of QZZG in the treatment of AIS.

A combined network pharmacology and metabolomics approach was used to predict the key targets and pathways of QZZG in the treatment of AIS and to elucidate the mechanism of QZZG through experimental validation.

In this study, QZZG improved histopathologic features and reduced infarct volume and neurologic deficit scores. Integrated network pharmacology and metabolomics revealed that QZZG may protect neurons by regulating glutamate and its receptors, and that glutamate is closely related to NMDAR1, NRF2, and Caspase-3. Pathway analysis results suggested that NMDAR-mediated Ca2+ inward flow is one of the critical pathways. In terms of neuroexcitotoxicity QZZG inhibited glutamate content, reduced Ca2+ inward flow, protected mitochondrial function, and reduced ROS, as well as being able to effectively inhibit the expression of NMDAR1, Caspase-3, Bax, and promote the expression of Bcl-2, NMDAR2A. In terms of ferroptosis QZZG promoted NRF2, HO-1, GPX4 and nuclear-NRF2, inhibited the expression of BACH1 and ACSL4, and suppressed Fe2+ accumulation and lipid peroxidation. Silencing of BACH1 resulted in elevated expression of NRF2 and decreased expression of ACSL4, which inhibited the sensitivity of neurons to ferroptosis. QZZG was able to further increase NRF2 expression under conditions of silencing BACH1. QZZG induced NRF2 and inhibited BACH1, ACSL4 was inhibited by ML385, and inhibition of NRF2 induced the expression of BACH1 and ACSL4, QZZG protects neurons in an NRF2-dependent manner.

In summary, QZZG inhibited neuroexcitotoxicity and ferroptosis by regulating the NMDAR/NRF2/BACH1/ACSL4 pathway. The study provided a relatively novel perspective on the mechanism of traditional Chinese medicine (TCM) treatment of the disease.

The transsulfuration (TSS) pathway is an alternative source of cysteine for glutathione synthesis. Little of the TSS pathway in antioxidant capacity in sickle cell disease (SCD) is known. Here, we evaluate the effects of TSS pathway activation through cystathionine beta-synthase (CBS) to attenuate reactive oxygen species (ROS) and ferroptosis stresses in SCD. A vital contribution of the TSS pathway in sustaining cysteine levels is detected only under hemin exposure or physiological but not supraphysiological cystine supplement. Mechanistic studies show that hemin suppresses CBS expression to inhibit the TSS pathway and de novo cysteine biosynthesis. By contrast, the expression of CBS is inducible by dimethyl fumarate (DMF) through nuclear factor erythroid 2-related factor 2 (NRF2) activation and CpG islands DNA hydroxymethylation. DMF induces the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) to downregulate L-2-hydroxyglutarate (L2HG) and increase global and locus-specific DNA hydroxymethylation levels. This DMF-upregulated DNA hydroxymethylation affects CBS locus chromatin structure modifications and upregulates gene expression. Our results suggest that CBS of the TSS pathway plays an important role in maintaining cysteine levels under restricted cystine availability or excess hemin exposure, and CBS upregulation by DMF increases the cellular glutathione levels to protect against ROS and ferroptosis stress in SCD.

Nasopharyngeal carcinoma (NPC) is one of the common malignant tumors in clinic. In the current study, we aim to investigate the effects of PRMT4 on erastin-induced ferroptosis in NPC by cisplatin resistant. PRMT4 expression in patients with NPC by cisplatin was upregulated. PRMT4 upregulation promoted cell growth of erastin-induced ferroptosis in NPC cisplatin-resistant cells. PRMT4 downregulation reduced cell growth of erastin-induced ferroptosis in NPC cisplatin-resistant cells. PRMT4 promoted tumor volume in mice model of erastin-induced NPC by cisplatin. PRMT4 upregulation reduced erastin-induced ferroptosis in NPC cisplatin-resistant cells by mitochondrial damage. PRMT4 upregulation induced Nrf2 protein expression in model of erastin-induced NPC by cisplatin. Nrf2 reduced the effects of si-PRMT4 on cell growth of erastin-induced ferroptosis in NPC cisplatin-resistant cells. Nrf2 inhibitor reduced the effects of PRMT4 on cell growth of erastin-induced ferroptosis in NPC cisplatin-resistant cells. Nrf2 reduced the effects of si-PRMT4 on erastin-induced ferroptosis in NPC cisplatin-resistant cells by mitochondrial damage. PRMT4 protein interlinked with Nrf2 protein to decrease Nrf2 ubiquitination. Methylation increased PRMT4 DNA stability. Collectively, our data reveal that PRMT4 reduced erastin-induced ferroptosis in NPC cisplatin-resistant cells by Nrf2/GPX4 pathway, suggesting that targeting PRMT4 may present as a potential strategy against the development of NPC.

Ferroptosis is a unique programmed cell death driven by iron-dependent phospholipid peroxidation. Tumor cells that escape from the conventional therapies appear more sensitive to ferroptosis. Therefore, it is extremely urgent to find safe and efficient active ingredients that induce ferroptosis in tumor cells. Herein, we identified that angelic acid, as a potent anti-tumor active ingredient in Angelica sinensis, profoundly sensitizes CRC cells to ferroptosis via a natural compound library screen. We revealed that angelic acid treatment is sufficient to predispose CRC cells to ferroptosis phenotype, evidenced by malondialdehyde (MDA) accumulation, lipid peroxidation, and upregulation of ferroptosis-associated markers CHAC1 and PTGS2, which is abolished by ferroptosis inhibitor Fer-1. Moreover, the results of network pharmacology showed that NRF2 is critical for angelic acid-mediated CRC cell ferroptosis. Mechanistically, angelic acid exerted its ferroptosis induction via directly binding and facilitating the degradation of NRF2. In addition, the syngeneic mouse models revealed that angelic acid boosts CRC cell sensitivity to ferroptosis inducer sulfasalazine with essentially no toxicity in vivo. Collectively, our findings highlighted a previously unrecognized anti-tumor mechanism of angelic acid and represented an appealing therapeutic strategy for CRC treatment.

RNA-sequencing and differential gene expression studies have significantly advanced our understanding of pathogenic pathways underlying rheumatoid arthritis (RA). Yet, little is known about cell-specific regulatory networks and their contributions to disease. In this study, we focused on fibroblast-like synoviocytes (FLS), a cell type central to disease pathogenesis and joint damage in RA. We used a strategy that computed sample-specific gene regulatory networks to compare network properties between RA and osteoarthritis FLS. We identified 28 transcription factors (TFs) as key regulators central to the signatures of RA FLS. Six of these TFs are new and have not been previously implicated in RA through ex vivo or in vivo studies, and included BACH1, HLX, and TGIF1. Several of these TFs were found to be co-regulated, and BACH1 emerged as the most significant TF and regulator. The main BACH1 targets included those implicated in fatty acid metabolism and ferroptosis. The discovery of BACH1 was validated in experiments with RA FLS. Knockdown of BACH1 in RA FLS significantly affected the gene expression signatures, reduced cell adhesion and mobility, interfered with the formation of thick actin fibers, and prevented the polarized formation of lamellipodia, all required for the RA destructive behavior of FLS. This study establishes BACH1 as a central regulator of RA FLS phenotypes and suggests its potential as a therapeutic target to selectively modulate RA FLS.

Ferroptosis is a form of cell death that occurs when there is an excess of reactive oxygen species (ROS), lipid peroxidation, and iron accumulation. The precise regulation of metabolic pathways, including iron, lipid, and amino acid metabolism, is crucial for cell survival. This type of cell death, which is associated with oxidative stress, is controlled by a complex network of signaling molecules and pathways. It is also implicated in various respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), lung cancer, pulmonary fibrosis (PF), and the coronavirus disease 2019 (COVID-19). To combat drug resistance, it is important to identify appropriate biological markers and treatment targets, as well as intervene in respiratory disorders to either induce or prevent ferroptosis. The focus is on the role of ferroptosis in the development of respiratory diseases and the potential of targeting ferroptosis for prevention and treatment. The review also explores the interaction between immune cell ferroptosis and inflammatory mediators in respiratory diseases, aiming to provide more effective strategies for managing cellular ferroptosis and respiratory disorders.

Subarachnoid hemorrhage (SAH) is a specific type of stroke. Dihydroquercetin (DHQ), a flavonoid, is known for its various pharmacological properties. This study aimed to explore the roles and mechanisms of DHQ in influencing the progression of SAH. A rat SAH model was established using the endovascular perforation technique. Following SAH induction, DHQ was administered orally 1 h later. Assessments included SAH scores, neurological function, brain swelling, blood-brain barrier (BBB) integrity, neuronal damage, apoptosis levels, inflammation, and indicators of ferroptosis using various treatments. The HT22 cells were exposed to hemin to simulate SAH-like conditions under in vitro settings. Cell counting kit-8 assays, flow cytometry, enzyme?linked immunosorbent assay, BODIPY 581/591 C11 staining, western blot analysis, and biochemical kits were employed to evaluate the potential effects of DHQ. Moreover, the mechanisms responsible for the protective effect of DHQ were examined by western blot analysis. The in vivo findings revealed that DHQ mitigated neurological impairments, brain swelling, BBB disruption, and neuronal injury at 24 h post-SAH. DHQ also reduced neuronal degeneration, inflammation, and ferroptosis following SAH. The in vitro findings revealed that DHQ enhanced cell survival and reduced ferroptosis at 24 h following hemin exposure. Mechanistically, DHQ activated phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in SAH rats and hemin-treated HT22 cells to exert neuroprotective effects. In conclusion, this study reveals that DHQ can effectively decrease BBB permeability, brain edema, neurological dysfunctions, and ferroptosis post-SAH by activating the PI3K/AKT/Nrf2/HO-1 pathway.

The term frontotemporal dementia (FTD) comprises a group of neurodegenerative disorders characterized by the progressive degeneration of the frontal and temporal lobes of the brain with language impairment and changes in cognitive, behavioral and executive functions, and in some cases motor manifestations. A high proportion of FTD cases are due to genetic mutations and inherited in an autosomal-dominant manner with variable penetrance depending on the implicated gene. Iron is a crucial microelement that is involved in several cellular essential functions in the whole body and plays additional specialized roles in the central nervous system (CNS) mainly through its redox-cycling properties. Such a feature may be harmful under aerobic conditions, since it may lead to the generation of highly reactive hydroxyl radicals. Dysfunctions of iron homeostasis in the CNS are indeed involved in several neurodegenerative disorders, although it is still challenging to determine whether the dyshomeostasis of this essential but harmful metal is a direct cause of neurodegeneration, a contributor factor or simply a consequence of other neurodegenerative mechanisms. Unlike many other neurodegenerative disorders, evidence of the dysfunction in brain iron homeostasis in FTD is still scarce; nonetheless, the recent literature intriguingly suggests its possible involvement. The present review aims to summarize what is currently known about the contribution of iron dyshomeostasis in FTD based on clinical, imaging, histological, biochemical and molecular studies, further suggesting new perspectives and offering new insights for future investigations on this underexplored field of research.

Ferroptosis is a cell death mechanism mediated by iron-dependent lipid peroxidation. Although ferroptosis has garnered attention as a cancer-suppressing mechanism, there are still limited markers available for identifying ferroptotic cells or assessing their sensitivity to ferroptosis. The study focused on biliverdin, an endogenous reducing substance in cells, and examined the dynamics of intracellular biliverdin during ferroptosis using a biliverdin-binding cyanobacteriochrome. It was found that intracellular biliverdin decreases during ferroptosis and that this decrease is specific to ferroptosis amongst different forms of cell death. Furthermore, the feasibility of predicting sensitivity to ferroptosis by measuring intracellular biliverdin was demonstrated using a ferroptosis model induced by the re-expression of the transcription factor BACH1. These findings provide further insight into ferroptosis research and are expected to contribute to the development of cancer therapies that exploit ferroptosis.

Ferroptosis is a form of regulated cell death characterized by iron-dependent phospholipid peroxidation and is closely related to various diseases. System Xc-, a cystine/glutamate antiporter, and glutathione peroxidase 4 (GPX4) are key molecules in ferroptosis. Erastin and RSL3, known as inhibitors of system Xc- and GPX4, respectively, are commonly used as ferroptosis inducers. Broad-Complex, Tramtrack and Bric a brac (BTB) and Cap'n'collar (CNC) homology 1 (BACH1), a heme-binding transcription repressor, promotes pro-ferroptotic signalling, and therefore, Bach1-deficient cells are resistant to ferroptosis. Irikura et al. (Ferroptosis model system by the re-expression of BACH1. J. Biochem. 2023;174:239-52) constructed Bach1-re-expressing immortalized mouse embryonic fibroblasts (iMEFs) from Bach1-/- mice, which induce ferroptosis simply through the depletion of 2-mercaptoethanol from the culture medium. Transcriptional repression by re-expressed BACH1 induces suppressed glutathione synthesis and increases labile iron. Furthermore, ferroptosis initiated by BACH1-re-expressing iMEFs is propagated to surrounding cells. Thus, the BACH1-re-expression system is a novel and powerful tool to investigate the cellular basis of ferroptosis.

Changes in the absolute protein amounts of transcription factors are important for regulating gene expression during cell differentiation and in responses to changes in the cellular and extracellular environment. However, few studies have focused on the absolute quantification of mammalian transcription factors. In this study, we established an absolute quantification method for the transcription factors BACH1 and BACH2, which are expressed in B cells and regulated by direct heme binding. The method used purified recombinant proteins as controls in western blotting and was applied to mouse naïve B cells in the spleen, as well as activated B cells and plasma cells. BACH1 was present in naïve B cells at approximately half the levels of BACH2. In activated B cells, BACH1 decreased compared to naïve B cells, whilst BACH2 increased. In plasma cells, BACH1 increased back to the same extent as in naïve B cells, whilst BACH2 was not detected. Their target genes, Prdm1 and Hmox1, were highly induced in plasma cells. BACH1 was found to undergo degradation with lower concentrations of heme than BACH2. Therefore, BACH1 and BACH2 are similarly abundant in B cells but differ in heme sensitivity, potentially regulating gene expression differently depending on their heme responsiveness.

Ferroptosis is a relatively recently discovered type of regulated cell death that is induced by iron-dependent lipid peroxidation. The key contributing factors to ferroptosis are the loss of glutathione peroxidase 4 which is required for reversing lipid peroxidation, the buildup of redox-active iron and the oxidation of phospholipids containing polyunsaturated fatty acids. Ferroptosis has been associated with a number of diseases, including cancers such as hepatocellular carcinoma, breast cancer, acute renal damage and neurological disorders such as Alzheimer's disease and Alzheimer's disease, and there may be an association between ferroptosis and acute myeloid leukemia (AML). The present review aims to describe the primary regulatory pathways of ferroptosis, and the relationship between ferroptosis and the occurrence and development of AML. Furthermore, the present review comprehensively summarizes the latest advances in the treatment and prognosis of ferroptosis in AML.

By critically examining the work, we conducted a comprehensive bibliometric analysis on the role of nuclear factor erythroid 2-related factor 2 (NRF2) in nervous system diseases. We also proposed suggestions for future bibliometric studies, including the integration of multiple websites, analytical tools, and analytical approaches, The findings presented provide compelling evidence that ferroptosis is closely associated with the therapeutic challenges of nervous system diseases. Targeted modulation of NRF2 to regulate ferroptosis holds substantial potential for effectively treating these diseases. Future NRF2-related research should not only focus on discovering new drugs but also on designing rational drug delivery systems. In particular, nanocarriers offer substantial potential for facilitating the clinical translation of NRF2 research and addressing existing issues related to NRF2-related drugs.

The unstability of selenium nanoparticles (SeNPs) results in decreased activity which limits its therapeutic potential. In this study, we utilized Ganoderma lucidum spore polysaccharide (GLP, Mw = 983.96 kDa) as a novel stabilizer to synthesize GLP-SeNPs. GLP-SeNPs (Se/GLP = 1/3) with an average diameter of 149 nm were successfully prepared and it was stable for at least 30 days at 4 °C. It exhibited an orange-red color, zero valence state, amorphous structure, selenium uniform distribution, a zeta potential of -29.73 mV, selenium content of 16.04 %. GLP-SeNPs pretreatment decreased lipid accumulation, reduced ROS content and enhanced SOD and CAT activity in HepG2 cells. Fe2+ and MDA contents were decreased, while GPX4 and GSH activities were increased. All these ameliorated effects could be abolished by NRF2 antagonist ML385. The expression of anti-oxidant genes and iron exporter was up-regulated, while that of pro-oxidant and lipid biosynthesis gene was down-regulated. The GPX4 activity could be reduced by ML385 addition. In conclusion, GLP-SeNPs was successfully constructed at the ratio of 1/3 (Se/GLP). It prevents MAFLD by targeting ferroptosis, including lowering iron overload, inhibiting lipid accumulation and attenuating oxidative stress. The improvement was conducted via activating SLC40A1-mediated iron pathway, ACSL4-mediated lipid metabolism and NRF2-mediated GSH-GPX4 pathway. Therefore, GLP-SeNPs can be used as potential selenium nutritional supplements or adjuvants for MAFLD prevention.

Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.

Reperfusion after myocardial infarction (MI) can lead to myocardial ischemia/reperfusion (I/R) damage. The transcription factor (TF) broad-complex, tramtrack, and bric-a-brac (BTB) and cap'n'collar (CNC) homology 1 (BACH1) is implicated in the injury. However, the downstream mechanisms of BACH1 in affecting myocardial hypoxia/reoxygenation (H/R) damage are still fully understood. AC16 cells were stimulated with H/R conditions to model cardiomyocytes under H/R. mRNA analysis was performed by quantitative real-time PCR. Protein levels were gauged by immunoblot analysis. The effect of BACH1/cyclin-dependent kinase inhibitor 3 (CDKN3) on H/R-evoked injury was assessed by measuring cell viability via Cell Counting Kit-8 (CCK-8), apoptosis (flow cytometry and caspase 3 activity), ferroptosis via Fe2+, glutathione (GSH), reactive oxygen species (ROS) and malondialdehyde (MDA) markers and inflammation cytokines interleukin-1beta (IL-1β) and tumor necrosis factor alpha (TNF-α). The BACH1/CDKN3 relationship was examined by chromatin immunoprecipitation (ChIP) experiment and luciferase assay. BACH1 was increased in MI serum and H/R-stimulated AC16 cardiomyocytes. Functionally, disruption of BACH1 mitigated H/R-evoked in vitro apoptosis, ferroptosis and inflammation of AC16 cardiomyocytes. Mechanistically, BACH1 activated CDKN3 transcription and enhanced CDKN3 protein expression in AC16 cardiomyocytes. Our rescue experiments validated that BACH1 disruption attenuated H/R-evoked AC16 cardiomyocyte apoptosis, ferroptosis and inflammation by downregulating CDKN3. Additionally, BACH1 disruption could activate the adenosine monophosphate-activated protein kinase (AMPK) signaling by downregulating CDKN3 in H/R-stimulated AC16 cardiomyocytes. Our study demonstrates that BACH1 activates CDKN3 transcription to induce H/R-evoked damage of AC16 cardiomyocytes partially via AMPK signaling.

Sepsis is a global health challenge that results in systemic inflammation, oxidative stress, and multi-organ dysfunction, with the heart being particularly susceptible. This study aimed to elucidate the effect of FTO, a key regulator in m6A methylation in septic cardiomyopathy, and its potential therapeutic implications. Cellular and animal models of septic myocardial injury were established. Moreover, it was revealed that ferroptosis, which is a form of programmed necrosis occurring with iron dependence, was activated within cardiomyocytes during septic conditions. The overexpression of FTO-suppressed ferroptosis alleviated heart inflammation and dysfunction and improved survival rates in vivo. However, the protective effects of FTO were attenuated by the overexpression of BACH1, which is a molecule negatively correlated with FTO. Mechanistically, FTO modulated the m6A modification of BACH1, suggesting a complex interplay in the regulation of cardiomyocyte damage and sepsis. Our findings reveal the potential of targeting the FTO/BACH1 axis and ferroptosis inhibitors as therapeutic strategies for sepsis-induced cardiac injuries.

The membrane lipid damage caused by reactive oxygen species(ROS) and various peroxides, namely lipid peroxidation, plays an important role in the progression of diabetic nephropathy (DN).We previously reported that vitamin D receptor(VDR) plays an active role in DN mice by modulating autophagy disorders. However, it is unclear whether the ATP-citrate lyase (ACLY)/NF-E2-related factor-2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway is associated with the reduction of lipid peroxidation by VDR in the DN model. We found that in the DN mouse model, VDR knockout significantly aggravated mitochondrial morphological damage caused by DN, increased the expression of ACLY, promoted the accumulation of ROS, lipid peroxidation products Malondialdehyde(MDA) and 4-hydroxy-2-nonenal (4-HNE),consumed the Nrf2/Keap1 system, thus increasing lipid peroxidation. However, the overexpression of VDR and intervention with the VDR agonist paricalcitol (Pari) can reduce the above damage. On the other hand, cellular experiments have shown that Pari can significantly reduce the elevated expression of ACLY and ROS induced by advanced glycation end products (AGE). However, ACLY overexpression partially eliminated the positive effects of the VDR agonist. Next, we verified the transcriptional regulation of ACLY by VDR through chromatin immunoprecipitation (ChIP)-qPCR and dual luciferase experiments. Moreover, in AGE models, knockdown of ACLY decreased lipid peroxidation and ROS production, while intervention with Nrf2 inhibitor ML385 partially weakened the protective effect of ACLY downregulation. In summary, VDR negatively regulates the expression of ACLY through transcription, thereby affecting the state of Nrf2/Keap1 system and regulating lipid peroxidation, thereby inhibiting kidney injury induced by DN.

During human embryogenesis, distinct waves of hematopoiesis give rise to various blood cell types, originating from hemogenic endothelial (HE) cells. As HE cells reside in hypoxic conditions in the embryo, we investigated the role of hypoxia in human endothelial to hematopoietic transition and subsequent hematopoiesis. Using single-cell RNA sequencing, we describe hypoxia-related transcriptional changes in different HE-derived blood lineages, which reveal that erythroid cells are particularly susceptible to oxidative stress, due to decreased NRF2 activity in hypoxia. In contrast, nonerythroid CD45+ cells exhibit increased proliferative rates in hypoxic conditions and enhanced resilience to oxidative stress. We find that even in normoxia, erythroid cells present a clear predisposition to oxidative stress, with low glutathione levels and high lipid peroxidation, in contrast to CD45+ cells. Intriguingly, reactive oxygen species are produced at different sites in GPA+ and CD45+ cells, revealing differences in oxidative phosphorylation and the use of canonical versus noncanonical tricarboxylic acid cycle in these lineages. Our findings elucidate how hypoxia and oxidative stress distinctly affect HE-derived hematopoietic lineages, uncovering critical transcriptional and metabolic pathways that influence blood cell development.

Intercellular adhesion molecule 1 (ICAM-1/CD54), a transmembrane glycoprotein, has been considered as one of the most important adhesion molecules during leukocyte recruitment. It is encoded by the ICAM1 gene and plays a central role in inflammation. Its crucial role in many inflammatory diseases such as ulcerative colitis and rheumatoid arthritis are well established. Given that neuroinflammation, underscored by microglial activation, is a key element in neurodegenerative diseases such as Parkinson's disease (PD), we investigated whether ICAM-1 has a role in this progressive neurological condition and, if so, to elucidate the underpinning mechanisms. Specifically, we were interested in the potential interaction between ICAM-1, glial cells, and ferroptosis, an iron-dependent form of cell death that has recently been implicated in PD. We conclude that there exist direct and indirect (via glial cells and T cells) influences of ICAM-1 on ferroptosis and that further elucidation of these interactions can suggest novel intervention for this devastating disease.

Gastric mucosal injury is a chronic and progressive stomach disease that can be caused by nonsteroidal anti-inflammatory drugs (NSAIDs). Therefore, there is an urgent need to find safe and effective drugs to prevent gastric mucosal injury due to NSAIDs. Cinnamaldehyde (CA) is a bioactive compound extracted from the rhizome of cinnamon and has various pharmacological functions, including anti-inflammatory, analgesic, antiapoptotic, and antioxidant activities. However, the potential pharmacological effect of CA on gastric mucosal injury remains unknown.

The aim of this study was to investigate the protective effects of CA on aspirin-induced gastric mucosal injury and to explore its mechanism of action METHODS: The effect of CA on gastric mucosal injury was investigated in vitro and in vivo, in vitro mouse model of gastric mucosal injury induced by aspirin, in vitro model of GES-1 cell injury by aspirin and Erastin. The mechanism of action of CA was determined using Transcriptomics and bioinformatics.

CA exerted its protective effects against gastric mucosal injury by modulating the downstream targets, including mTOR, GSK3β, and NRF2, via the PI3K/AKT signaling pathway to inhibit autophagy, apoptosis, and ferroptosis in the gastric epithelial cells. Further cellular experiments confirmed that the PI3K/AKT pathway was a key target for CA against gastric mucosal injury.

This study provides the first evidence of CA, an active compound in cinnamon, possessing therapeutic potential in preventing and treating gastric mucosal injury, with its mechanism involving the regulation of apoptosis, autophagy, and ferroptosis in gastric epithelial cells mediated by the PI3K/AKT signaling pathway.

NRF2 is an important transcription factor that regulates redox homeostasis in vivo and exerts its anti-oxidative stress and anti-inflammatory response by binding to the ARE to activate and regulate the transcription of downstream protective protein genes, reducing the release of reactive oxygen species. Ferroptosis is a novel iron-dependent, lipid peroxidation-driven cell death mode, and recent studies have shown that ferroptosis is closely associated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). NRF2 is able to regulate ferroptosis through the regulation of the transcription of its target genes to ameliorate ALI/ARDS. Therefore, This article focuses on how NRF2 plays a role in ALI/ARDS by regulating ferroptosis. We further reviewed the literature and deeply analyzed the signaling pathways related to ferroptosis which were regulated by NRF2. Additionally, we sorted out the chemical molecules targeting NRF2 that are effective for ALI/ARDS. This review provides a relevant theoretical basis for further research on this theory and the prevention and treatment of ALI/ARDS. The intended audience is clinicians and researchers in the field of respiratory disease.

Ferroptosis is a type of regulated cell death characterized by iron-dependent lipid peroxidation. A model cell system is constructed to induce ferroptosis by re-expressing the transcription factor BACH1, a potent ferroptosis inducer, in immortalized mouse embryonic fibroblasts (iMEFs). The transfer of the culture supernatant from ferroptotic iMEFs activates the proliferation of hepatoma cells and other fibroblasts and suppresses cellular senescence-like features. The BACH1-dependent secretion of the longevity factor FGF21 is increased in ferroptotic iMEFs. The anti-senescent effects of the culture supernatant from these iMEFs are abrogated by Fgf21 knockout. BACH1 activates the transcription of Fgf21 by promoting ferroptotic stress and increases FGF21 protein expression by suppressing its autophagic degradation through transcriptional Sqstm1 and Lamp2 repression. The BACH1-induced ferroptotic FGF21 secretion suppresses obesity in high-fat diet-fed mice and the short lifespan of progeria mice. The inhibition of these aging-related phenotypes can be physiologically significant regarding ferroptosis.