Redox Biology最新文献

{"title":"OseR, a bacterial redox sensor, regulates ergothioneine uptake via a Cys thiol switch, enhancing oxidative stress resistance and virulence","authors":"Xinchi Zhu ,&nbsp;Yifan Wu ,&nbsp;Huochun Yao ,&nbsp;Zongfu Wu","doi":"10.1016/j.redox.2025.103790","DOIUrl":"10.1016/j.redox.2025.103790","url":null,"abstract":"<div><div>Ergothioneine (ET), a low-molecular-weight (LMW) thiol, serves as a potent antioxidant. While only a limited number of Actinomycetes and fungi can synthesize ET, most microorganisms acquire it from external sources. Recently, a microbial ET transporter system (EtUV) was identified in <em>Helicobacter pylori</em> and <em>Streptococcus pneumoniae</em>, but the regulatory mechanisms controlling EtUV in bacteria remain unknown. In this study, we identified and characterized OseR, a novel MarR family repressor in <em>Streptococcus suis</em>, a significant pathogen causing systemic diseases such as septicemia and meningitis in pigs and humans. We demonstrated that OseR senses oxidative stress through a thiol switch at Cys35, which regulates the ET transport system EtUV. Under oxidative stress, OseR dissociates from the promoter region of the ET transport operon due to the formation of an intermolecular disulfide bond, leading to the activation of EtUV expression. Our findings reveal that OseR not only controls ET transport but also modulates other LMW thiol transport pathways, including glutathione and cysteine, as well as genes involved in oxidative stress responses. Deletion or mutation of <em>oseR</em> significantly impairs oxidative stress tolerance, survival in mouse macrophages, and virulence in mice. Similarly, deletion or mutation of <em>etU</em>, which encodes a transmembrane permease essential for ET uptake, markedly reduces oxidative stress tolerance and virulence in mice. Importantly, our results suggest that OseR-mediated regulation of the ET transport system, driven by a thiol-based switch, may be conserved across bacterial species, highlighting a broader role for OseR in bacterial adaptation to host environments. This study advances our understanding of the regulatory mechanisms governing ET uptake in bacteria and provides new insights into the link between ET and bacterial pathogenicity.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103790"},"PeriodicalIF":11.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arylsulfatase K attenuates airway epithelial cell senescence in COPD by regulating parkin-mediated mitophagy","authors":"Ruonan Yang ,&nbsp;Yuan Zhan ,&nbsp;Zhesong Deng ,&nbsp;Jiaheng Zhang ,&nbsp;Shanshan Chen ,&nbsp;Yating Zhang ,&nbsp;Hao Fu ,&nbsp;Xiangling Meng ,&nbsp;Jixing Wu ,&nbsp;Yiya Gu ,&nbsp;Qian Huang ,&nbsp;Congyi Wang ,&nbsp;Jungang Xie","doi":"10.1016/j.redox.2025.103793","DOIUrl":"10.1016/j.redox.2025.103793","url":null,"abstract":"<div><div>Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by irreversible airflow limitation, primarily due to cigarette smoke (CS) exposure. Emerging research underscores the pivotal role of cellular senescence in the pathogenesis of COPD. The arylsulfatase family, known for its involvement in various age-related diseases, has yet to be investigated in the context of COPD. This study investigated the role of the arylsulfatase family, particularly ARSK, in COPD pathogenesis. Bioinformatics analysis and clinical validation revealed significantly reduced ARSK expression in COPD patients' lungs, especially in airway epithelium. ARSK overexpression alleviated CS-induced epithelial cellular senescence and improved mitophagy and mitochondrial function, while ARSK knockdown had an opposite effect. In <em>vivo</em>, Arsk-AAV administration relieved lung senescence and impaired lung function upon CS exposure, whereas airway-specific Arsk knockout aggravated these effects. Mechanistically, ARSK interacted with Parkin (PRKN) to regulate the phosphorylation of PRKN at serine 65 and subsequent mitophagy, thus attenuating cellular senescence. Additionally, the androgen receptor (AR) was identified as a transcription factor binding to the ARSK promoter, modulating its expression. These findings highlight the protective role of ARSK against epithelial cellular senescence, offering a potential therapeutic target for COPD.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103793"},"PeriodicalIF":11.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heme bound to the bacterial transcription factor SqrR/YgaV catalyzes oxygen-dependent conversion of hydrogen sulfide to polysulfide for regulated gene expression","authors":"Ryoma Iwata,&nbsp;Shinji Masuda","doi":"10.1016/j.redox.2025.103801","DOIUrl":"10.1016/j.redox.2025.103801","url":null,"abstract":"<div><div>Hydrogen sulfide (H₂S) and polysulfide are critical signaling molecules in bacteria, with distinct roles in regulating oxidative stress and redox balance. This study investigates the molecular mechanisms underlying the sulfur sensing and regulatory functions of two homologous transcription factors, SqrR from <em>Rhodobacter capsulatus</em> and YgaV from <em>Escherichia coli</em>. <em>In vitro</em> thiol-specific labeling and SDS–PAGE analyses demonstrate that apo-SqrR and apo-YgaV respond selectively and sensitively to polysulfides, rather than H₂S itself, under both aerobic and anaerobic conditions. UV–visible spectroscopy demonstrated that the coordination state of the heme changes depending on the cysteine redox status: reduced cysteines support a six-coordinate heme, while oxidation to tetrasulfide crosslink leads to a five-coordinate state. Importantly, heme binding enhances cysteine oxidation by H₂S under aerobic conditions, but not under anaerobic conditions, indicating that oxygen facilitates heme-mediated generation and utilization of polysulfides. In contrast, heme binding suppresses cysteine reactivity toward polysulfides under anaerobic conditions in both proteins, with this suppression modulated by the redox state of the heme iron. These findings suggest that heme binding regulates sulfur responsiveness by promoting cysteine oxidation by H₂S under aerobic conditions and suppressing polysulfide reactivity under anaerobic conditions. This work reveals a context-dependent regulatory mechanism by which bacterial transcription factors integrate redox cues and sulfur metabolism, shedding light on their evolutionary adaptation to fluctuating oxygen and sulfur environments.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103801"},"PeriodicalIF":11.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nrf2/Nlrp3 signaling in aging BMSCs: Traf6 intervention as a novel approach to osteoporosis treatment","authors":"Yajun Li ,&nbsp;Yunshang Yang ,&nbsp;Donglong Xia ,&nbsp;Yiling Fang ,&nbsp;Cheng Tang ,&nbsp;Jingxian Yu ,&nbsp;Dechun Geng ,&nbsp;Zhirong Wang ,&nbsp;Long Xiao","doi":"10.1016/j.redox.2025.103804","DOIUrl":"10.1016/j.redox.2025.103804","url":null,"abstract":"<div><div>Senile osteoporosis progression is closely related to the decreased osteogenic differentiation capacity of senescent bone marrow stromal stem cells (BMSCs). This study demonstrated that the Traf6-mediated Nrf2/Nlrp3 signaling axis significantly influences inflammatory senescence progression in BMSCs, and targeting Traf6 can effectively alleviate bone loss caused by inflammatory senescence. High-throughput sequencing revealed that primary BMSCs from 18Ms mice were differentially enriched in anti-inflammatory, antioxidant, and immune-related biological processes compared to those from young mice, with significant differences in the protein expression of Traf6, Nrf2, and Nlrp3-related pathways, indicating potential crosstalk. In vitro experiments using western blotting and immunofluorescence confirmed high levels of intracellular inflammation, oxidative stress, and elevated expression of Traf6, Nrf2, and Nlrp3 inflammatory vesicles in senescent BMSCs. We used lentiviral transfection to knockdown Traf6 and intervention with Nrf2 agonists and inhibitors, and we verified the regulation of the expression of Nrf2/Nlrp3 inflammatory vesicles by Traf6 and its effect on inflammatory senescence progression in BMSCs. We performed in vivo experiments involving targeted Traf6 knockdown in bone tissue, morphological analysis of the femur by micro-computed tomography and immunohistochemistry, measurement of serum MDA and bone metabolism-related indices using ELISA, and calcein labeling to observe the calcium salt deposition rate. These experiments confirmed that the Traf6-mediated Nrf2/Nlrp3 signaling axis significantly influences the inflammatory senescence of BMSCs. Targeting Traf6 effectively alleviates bone loss caused by inflammatory senescence, presenting a potential method for preventing and controlling senile osteoporosis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103804"},"PeriodicalIF":11.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clock gene ARNTL2 enhances 5-fluorouracil resistance in colon cancer by upregulating SLC7A11 to suppress ferroptosis","authors":"Jingbang Yang ,&nbsp;Dagui Lin ,&nbsp;Yulin Huang ,&nbsp;Shasha Yin ,&nbsp;Miao Chen ,&nbsp;Haohui Sun ,&nbsp;Wancui Zhu ,&nbsp;Enni Chen ,&nbsp;Yizhang Deng ,&nbsp;Enen Zhao ,&nbsp;Fulong Wang ,&nbsp;Linjie Zhang ,&nbsp;Wuguo Deng ,&nbsp;Liren Li","doi":"10.1016/j.redox.2025.103798","DOIUrl":"10.1016/j.redox.2025.103798","url":null,"abstract":"<div><div>Colorectal cancer, a leading cause of global cancer-related morbidity and mortality, poses a significant challenge with its incidence rising. 5-fluorouracil (5-FU), a key chemotherapy agent, faces the challenge of drug resistance. Clock genes, which regulate circadian rhythms, are linked to tumor occurrence, progression, and treatment responses, and are often abnormally expressed in many tumors. Ferroptosis, a non-apoptotic form of cell death, plays a role in tumor drug resistance. Recent research indicates that clock genes may influence tumor cells' sensitivity to ferroptosis by regulating cellular metabolism and oxidative stress responses. Through bioinformatics analysis, we identified the clock gene ARNTL2 as a key factor associated with chemoresistance. ARNTL2 was found to be significantly overexpressed in colon cancer, and was closely correlated with poor prognosis. Experimental validation using in vitro and in vivo models demonstrated that ARNTL2 promotes resistance to 5-FU by upregulating SLC7A11, a critical regulator of ferroptosis. Mechanistically, ARNTL2 directly binds to the SLC7A11 promoter and enhances its transcription, while also influencing SLC7A11 mRNA stability through PHGDH. These findings establish the ARNTL2-SLC7A11 axis as an important mechanism driving ferroptosis resistance and chemoresistance in colon cancer. Furthermore, we explored the therapeutic potential of melatonin (Mlt), a circadian-regulating hormone, and discovered that Mlt can degrade ARNTL2 via the ubiquitination-proteasome pathway, thereby downregulating the ARNTL2-SLC7A11 axis. Our results highlight ARNTL2 as a promising biomarker for predicting chemoresistance and prognosis in colon cancer patients. Additionally, the ability of Mlt to enhance chemotherapy sensitivity by targeting the ARNTL2-SLC7A11 axis offers a novel, low-toxicity strategy for improving treatment outcomes. These findings bridge the fields of chronobiology and oncology, providing new insights for precision medicine approaches in colon cancer.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103798"},"PeriodicalIF":11.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S-nitros(yl)ation of CaMKIIα and its precision redox regulation by SNOTAC plays a critical role in learning and memory","authors":"Boyu Chu ,&nbsp;Xinhua Qiao ,&nbsp;Hui Ye ,&nbsp;Xiaoli Cui ,&nbsp;Shuli Zhang ,&nbsp;Wenting Su ,&nbsp;Yuying Zhang ,&nbsp;Chuanxin Sun ,&nbsp;Xuanhao Wu ,&nbsp;Tiepeng Wang ,&nbsp;Hua Li ,&nbsp;Jianbing Wu ,&nbsp;Zhangjian Huang ,&nbsp;Chang Chen","doi":"10.1016/j.redox.2025.103784","DOIUrl":"10.1016/j.redox.2025.103784","url":null,"abstract":"<div><div>Ca²⁺/calmodulin-dependent protein kinase II α (CaMKIIα) and nitric oxide (NO) both play vital roles in learning and memory; however, the underlying mechanisms connecting them have remained elusive. To address this question, our study surprisingly observed that during learning and memory tasks, <em>S</em>-nitrosation of CaMKIIα, a key redox-based post-translational modification, significantly increased in mouse hippocampus. We then constructed mice with mutations in the major <em>S</em>-nitrosation sites of CaMKIIα (C280/289V) and found that the mutant mice exhibited remarkable cognitive impairments and attenuated long-term potentiation (LTP). Mechanistically, we demonstrated that the SNO-CaMKIIα mutation increased presynaptic release probability by increasing the interaction and the phosphorylation of synapsin I (Syn1). Excessive vesicle release in the resting state leads to invalid postsynaptic activation, resulting in reduced variability in postsynaptic AMPAR-mediated transmission and impaired response capacity of learning and memory. This reduction of response capacity was also detected in naturally aging mice, indicating it may serve as a determining factor underlying cognitive impairments. Furthermore, we developed the <em>S</em>-nitrosation targeting chimera (SNOTAC), a precision redox modulator designed to enhance the interaction between CaMKIIα and nNOS. Intranasal administration of SNOTAC increased the CaMKIIα <em>S</em>-nitrosation level in mouse hippocampus and successfully rescued learning and memory impairment. These findings establish that redox modification, CaMKIIα <em>S</em>-nitrosation, plays a vital, yet previously unrecognized role in the physiological processes of learning and memory. Moreover, the SNOTAC strategy pioneers a novel paradigm for precision redox intervention, highlighting the potential of targeted redox modulation for cognitive impairment.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103784"},"PeriodicalIF":11.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pancreatic stellate cells have adipogenic and fibrogenic potentials but only show increased pro-fibrogenic propensity upon aging","authors":"George A. Soultoukis ,&nbsp;Marina Leer ,&nbsp;Richard Kehm ,&nbsp;Laura Villacorta ,&nbsp;Vladimir Benes ,&nbsp;Tilman Grune ,&nbsp;Annika Höhn ,&nbsp;Tim J. Schulz","doi":"10.1016/j.redox.2025.103791","DOIUrl":"10.1016/j.redox.2025.103791","url":null,"abstract":"<div><div>Steatosis and fibrosis are two key pathological features of the aging pancreas that contribute to inflammation, metabolic dysfunction and degenerative changes of the tissue. Pancreatic stellate cells (SCs) are thought to be the main cellular source of ectopic adipocytes and fibrotic structures. SCs are fibroblast-like mesenchymal cells that reside in various microanatomies of the tissue and whose task under healthy, homeostatic conditions is to generate extracellular matrix (ECM) and maintenance signals to ensure tissue integrity and function. To examine pathological changes of the aging pancreas, we conducted single cell RNA-sequencing to analyze murine pancreatic cell heterogeneity and examined morphological changes of the aging exocrine pancreas, comparing young adult and aged wildtype mice. We specifically focused our analyses on SCs and their cellular interaction partners and mechanisms of paracrine crosstalk. Age-dependent transcriptional differences in these cell types occur on the level of ECM-related and pro-fibrotic expression signatures mediated through transforming growth factor (TGF) and platelet-derived growth factor (PDGF) signaling pathways. SCs can be divided into distinct subsets of activated (aSCs) and quiescent stellate cells (qSCs), based on distinct expression signatures and transcript levels of <em>Pdgfra</em> and <em>Pdgfrb</em>, which encode for the PDGF receptor alpha and -beta paralogs. Activated SCs, which display PDGF receptor alpha (PDGFRα) on their surface, exhibited subsets that appeared to be either pro-adipogenic or pro-fibrogenic at the transcriptomic level and aging promoted a pro-fibrogenic switch in aSCs. We conclude that pancreatic SCs are contributors to the age-related decline of the exocrine pancreas through an increased contribution of a pro-fibrotic microenvironment.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103791"},"PeriodicalIF":11.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dimethyl malonate preserves brain and neurobehavioral phenotype following neonatal hypoxia–ischemia by inhibiting FTH1-mediated ferritinophagy","authors":"Yiming Jin ,&nbsp;Xinxin Wang ,&nbsp;Xiaowen Xu ,&nbsp;Xiuwen Zhou ,&nbsp;Qing Wang ,&nbsp;Li Zhang ,&nbsp;Lili Li ,&nbsp;Meifang Jin ,&nbsp;Hong Ni","doi":"10.1016/j.redox.2025.103792","DOIUrl":"10.1016/j.redox.2025.103792","url":null,"abstract":"<div><h3>Background</h3><div>Hypoxic–ischemic brain damage (HIBD) is a predominant cause of neuronal injury and mortality in newborns. Current preventive and therapeutic interventions demonstrate limited clinical efficacy. Emerging evidence reveals ferroptosis as a critical mechanism within HIBD pathophysiology, positioning it as a promising therapeutic target. Dimethyl malonate (DMM), a competitive inhibitor of succinate dehydrogenase, has demonstrated neuroprotective properties across multiple models of neurological disorders. However, the impact of DMM on the neonatal HIBD has not been studied.</div></div><div><h3>Aim</h3><div>To investigate the neuroprotective effects of DMM against neonatal HIBD and elucidate its mechanisms of action.</div></div><div><h3>Methods</h3><div>We created a model of HIBD in neonatal male C57BL/6J mice and administered various doses of DMM or vehicle control. Quantitative assessments included cerebral infarct volume measurement, Nissl staining for neurons, neurological behavior, ferrous ion (Fe²⁺), malondialdehyde (MDA) level, 4-hydroxynonenal (4-HNE) expression, and solute carrier family 7 member 11 (SLC7A11, system Xc⁻)/glutathione peroxidase 4 (GPX4) antioxidant axis expression level. Parallel studies in vitro employed oxygen-glucose deprivation/reperfusion-treated HT22 cells to investigate the effects of DMM on ferroptosis and its underlying mechanisms. Moreover, key factors of ferritinophagy, including nuclear receptor coactivator 4 (NCOA4), SQSTM1/p62, ferritin heavy chain 1 (FTH1), and microtubule-associated protein light 3 II (LC3II) were analyzed by western blotting. Molecular interactions between NCOA4 and FTH1 in brain cortical tissues of DMM-treated HIBD mice were analyzed by coimmunoprecipitation (Co-IP). Ferroptosis regulation by DMM was further investigated via <em>Fth1</em> knockdown in cellular models. Immunofluorescence staining was used to evaluate the capacity of DMM to suppress ferritin degradation and lysosomal Fe²⁺ accumulation at the organelle level.</div></div><div><h3>Results</h3><div>DMM treatment demonstrated its neuroprotective efficacy in HIBD models, as evidenced by a reduction in cerebral infarct volume, an increase in the number of Nissl-positive neurons, and improved cognitive and motor functions in neonatal mice compared with controls. Additionally, the DMM intervention significantly modulated ferroptosis-related biomarkers in brain cortical tissues and HT22 cells, decreasing ferrous ion (Fe²⁺) accumulation, reducing lipid peroxidation products (MDA and 4-HNE), and enhancing SLC7A11/GPX4 antioxidant system activity. Importantly, DMM specifically regulated core ferritinophagy components: suppressing NCOA4 and LC3II expression while upregulating FTH1 and p62 levels. Co-IP revealed that mechanistically, DMM disrupted the protein interaction between NCOA4 and FTH1, effectively inhibiting ferritinophagy progression. The effects of antiferropto","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103792"},"PeriodicalIF":11.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144738358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATF7IP inhibits Sorafenib-induced ferroptosis in hepatocellular carcinoma cells by inhibiting CYB5R2 transcription and stabilizing PARK7 protein","authors":"Yijie Su ,&nbsp;Sirui Huang ,&nbsp;Yang Duan ,&nbsp;Liang Zhang ,&nbsp;Shengyun Feng ,&nbsp;Yingge Lv ,&nbsp;Bei Lan ,&nbsp;Chenghao Xuan","doi":"10.1016/j.redox.2025.103786","DOIUrl":"10.1016/j.redox.2025.103786","url":null,"abstract":"<div><div>Ferroptosis, an iron-dependent form of programmed cell death, arises from the accumulation of lipid peroxides at toxic levels. Sorafenib, a first-line treatment for advanced hepatocellular carcinoma, shows limited clinical efficacy due to drug resistance. However, the mechanisms underlying Sorafenib resistance, especially related to ferroptosis, remain poorly understood. In this study, we identify activating transcription factor 7-interacting protein (ATF7IP) as a key inhibitor of ferroptosis. ATF7IP depletion promotes Sorafenib-induced ferroptosis, resulting in decreased cell viability, reduced cellular glutathione (GSH) levels, increased lipid peroxidation, and altered mitochondrial crista structure. Notably, <em>ATF7IP</em> knockdown shows cooperative effects with Sorafenib in inhibiting hepatocellular carcinoma growth in mice. Mechanistically, ATF7IP interacts with SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) to epigenetically silence the transcription of cytochrome <em>b</em>5 reductase 2 (CYB5R2), thereby reducing cellular Fe²⁺ levels. Meanwhile, ATF7IP stabilizes the antioxidant sensor Parkinsonism-associated deglycase (PARK7) protein which preserves the transsulfuration pathway to produce GSH, also leading to the inhibition of Sorafenib-induced ferroptosis. In conclusion, our findings identify ATF7IP as a critical ferroptosis inhibitor and represent ATF7IP as a novel therapeutic target for Sorafenib-based combination therapies of hepatocellular carcinoma.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103786"},"PeriodicalIF":10.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding Parkinson's Disease: The interplay of cell death pathways, oxidative stress, and therapeutic innovations","authors":"Tingting Liu ,&nbsp;Xiangrui Kong ,&nbsp;Junbo Qiao ,&nbsp;Jianshe Wei","doi":"10.1016/j.redox.2025.103787","DOIUrl":"10.1016/j.redox.2025.103787","url":null,"abstract":"<div><div>Parkinson's disease (PD), a complex neurodegenerative disorder characterized by selective loss of substantia nigra (SN) dopaminergic neurons, pathological aggregation of α-synuclein (α-syn), and chronic neuroinflammation, is fundamentally driven by redox imbalance and oxidative stress. Recent studies reveal that a dynamic interplay of programmed and non-programmed cell death mechanisms—amplified by oxidative damage—drives PD progression. Programmed cell death pathways include apoptosis (caspase-dependent mitochondrial/extrinsic pathways), necroptosis (eceptor-interacting serine/threonine-protein kinase 1 (RIPK1)/RIPK3/mixed lineage kinase domain-like protein (MLKL) axis), pyroptosis (NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome/Gasdermin D (GSDMD)-mediated pore formation), PARthanatos (DNA damage-poly ADP-ribose polymerase (PARP-1)/apoptosis-inducing factor (AIF) cascade), ferroptosis (redox imbalance-driven lipid peroxidation/glutathione peroxidase 4 (GPX4) inactivation), disulfidptosis (disulfide stress from cystine metabolic collapse), and cuproptosis (mitochondrial lipoylated protein toxicity via copper-mediated oxidative damage), while non-programmed necrosis is triggered by energy collapse and calcium overload. Mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and oxidative stress act as central redox hubs, integrating multiple death pathways through reactive oxygen species (ROS) bursts (O₂·^-, H₂O₂, ·OH), calcium dysregulation, and metabolic abnormalities, forming a self-amplifying vicious cycle. Non-neuronal cells (e.g., microglia and astrocytes) exacerbate neuronal redox damage by releasing pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β)), dysregulating iron/copper metabolism (enhancing Fenton chemistry), and suppressing autophagic flux. Therapeutic strategies targeting redox-critical nodes include caspase/RIPK1 inhibition, GPX4 activators, autophagy modulators (rapamycin), acid β-glucocerebrosidase (GBA1) restoration, iron/copper chelators, and antioxidants (N-acetylcysteine) to restore glutathione homeostasis. Additionally, regulating glial polarization (triggering receptor expressed on myeloid cells 2 (TREM2) agonists) may disrupt inflammation-redox-death loops. Future challenges include deciphering spatiotemporal heterogeneity of cell death, developing multi-target redox therapies, and advancing biomarker-driven precision medicine (circulating free DNA (cfDNA), <em>p</em>-MLKL). Targeting redox dysregulation will guide breakthrough PD therapies.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103787"},"PeriodicalIF":10.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144702215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}