Redox Biology最新文献

{"title":"Macrophage Dvl2 deficiency promotes NOD1-Driven pyroptosis and exacerbates inflammatory liver injury","authors":"Xiaoye Qu ,&nbsp;Dongwei Xu ,&nbsp;Tao Yang ,&nbsp;Yizhu Tian ,&nbsp;Christopher T. King ,&nbsp;Xiao Wang ,&nbsp;Mingwei Sheng ,&nbsp;Yuanbang Lin ,&nbsp;Xiyun Bian ,&nbsp;Changyong Li ,&nbsp;Longfeng Jiang ,&nbsp;Qiang Xia ,&nbsp;Douglas G. Farmer ,&nbsp;Bibo Ke","doi":"10.1016/j.redox.2024.103455","DOIUrl":"10.1016/j.redox.2024.103455","url":null,"abstract":"<div><div>Dishevelled 2 (Dvl2) is a key mediator of the Wingless/Wnt signaling pathway that regulates cell proliferation, migration, and immune function. However, little is known about the role of macrophage Dvl2 in modulating NOD1-mediated pyroptosis and hepatocyte death in oxidative stress-induced inflammatory liver injury. In a mouse model of oxidative stress<em>-induced liver inflammation</em>, mice with myeloid-specific Dvl2 knockout (Dvl2^M−KO) displayed exacerbated ischemia/reperfusion (IR) stress-induced hepatocellular damage with increased serum ALT levels, oxidative stress, and proinflammatory mediators. Unlike in Dvl2^FL/FL controls, Dvl2^M−KO enhanced NOD1, caspase-1, GSDMD, and NF-κB activation in liver macrophages after IR. Interestingly, IR stress enhanced YAP colocalized with HSF1 in Dvl2^FL/FL macrophages, while macrophage Dvl2 deficiency reduced YAP and HSF1 colocalization in the nucleus under inflammatory conditions. Importantly, Dvl2 deletion diminished nuclear YAP interacted with HSF1 and augmented NOD1/caspase-1 and GSDMD activation in response to inflammatory stimulation. However, Dvl2 activation increased YAP interaction with HSF1 and activated HSF1 target gene eEF2, inhibiting NOD1/caspase-1, GSDMD, and NF-κB activity. Moreover, macrophage eEF2 deletion increased the NOD1-caspase-1 interaction, GSDMD activation, HMGB1 release, and hepatocyte LDH release after macrophage/hepatocyte co-culture. Adoptive transfer of eEF2-expressing macrophages in Dvl2^M−KO mice alleviated IR-triggered liver inflammation and hepatocellular damage. Therefore, macrophage Dvl2 deficiency promotes NOD1-mediated pyroptosis and exacerbates IR-induced hepatocellular death by disrupting the YAP-HSF1 axis. eEF2 is crucial for modulating NOD1-driven pyroptosis, inflammatory response, and hepatocyte death. Our findings underscore a novel role of macrophage Dvl2 in modulating liver inflammatory injury and imply the therapeutic potential in organ IRI and transplant recipients.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103455"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hsa-miR-532-3p protects human decidual mesenchymal stem cells from oxidative stress in recurrent spontaneous abortion via targeting KEAP1","authors":"Hong Zhou ,&nbsp;Jiaxin Zhou ,&nbsp;ShanShan Liu ,&nbsp;Jing Niu ,&nbsp;Jinghua Pan ,&nbsp;Ruiman Li","doi":"10.1016/j.redox.2025.103508","DOIUrl":"10.1016/j.redox.2025.103508","url":null,"abstract":"<div><h3>Background</h3><div>Human decidual mesenchymal stem cells (hDMSCs) play crucial roles in pregnancy. The decreased resistance of hDMSCs to oxidative stress is a key factor contributing to recurrent spontaneous abortion (RSA). miRNAs have essential functions in the proliferation and apoptosis of decidual tissues. However, the miRNAs involved in regulating oxidative stress in hDMSCs remain unclear.</div></div><div><h3>Methods</h3><div>Decidual tissues and hDMSCs were collected from patients with RSA and early pregnancy miscarriages. We assessed the antioxidant capacity of hDMSCs in both groups by detecting relevant indicators. Furthermore, differentially expressed miRNAs in hDMSCs were analyzed through miRNA sequencing. We evaluated the interaction between hsa-miR-532-3p and KEAP1 using a luciferase reporter assay. A mouse model of RSA was constructed for confirmation. Finally, we analyzed the correlations between serum hsa-miR-532-3p levels and the clinical features of pregnant women with RSA.</div></div><div><h3>Results</h3><div>miRNA sequencing revealed 44 miRNAs whose expression was downregulated and 9 miRNAs whose expression was upregulated in hDMSCs from the RSA group compared with those from the control group. The overexpression of hsa-miR-532-3p led to a significantly increased antioxidant capacity in hDMSCs. The knockdown or overexpression of hsa-miR-532-3p led to the upregulation or downregulation of KEAP1 expression, respectively. In a mouse model, the overexpression of hsa-miR-532-3p reduced embryo absorption rates in RSA mice, decreased KEAP1 expression levels in decidual tissues, and concurrently enhanced the resistance to oxidative stress. Furthermore, in patients diagnosed with RSA, serum hsa-miR-532-3p levels were significantly and negatively correlated with the gestational age.</div></div><div><h3>Conclusions</h3><div>Our study revealed a lower expression level of hsa-miR-532-3p in the hDMSCs of patients with RSA. Moreover, hsa-miR-532-3p protects hDMSCs from oxidative stress by targeting the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (KEAP1/NRF2) pathway. Hsa-miR-532-3p is closely related to gestational age and has good predictive value for identifying RSA.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103508"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143145355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AKRs confer oligodendrocytes resistance to differentiation-stimulated ferroptosis","authors":"Valentina Saverio ,&nbsp;Emanuele Ferrario ,&nbsp;Romina Monzani ,&nbsp;Mara Gagliardi ,&nbsp;Francesco Favero ,&nbsp;Davide Corà ,&nbsp;Claudio Santoro ,&nbsp;Marco Corazzari","doi":"10.1016/j.redox.2024.103463","DOIUrl":"10.1016/j.redox.2024.103463","url":null,"abstract":"<div><div>Ferroptosis is a recently characterized form of cell death that has gained attention for its roles in both pathological and physiological contexts. The existence of multiple anti-ferroptotic pathways in both neoplastic and healthy cells, along with the critical regulation of iron metabolism involved in lipid peroxides (lipid-ROS) production—the primary mediators of this cell death process—underscores the necessity of precisely controlling or preventing accidental/unwanted ferroptosis. Conversely, dysregulated iron metabolism and alterations in the expression or activity of key anti-ferroptotic components are linked to the development and progression of various human diseases, including multiple sclerosis (MS). In MS, the improper activation of ferroptosis has been associated with the progressive loss of myelinating oligodendrocytes (myOLs). Our study demonstrates that the physiological and maturation-dependent increase in iron accumulation within oligodendrocytes acts as a pro-ferroptotic signal, countered by the concurrent expression of AKR1C1. Importantly, MS-related neuroinflammation contributes to the down-regulation of AKR1C1 through miRNA-mediated mechanisms, rendering mature oligodendrocytes more vulnerable to ferroptosis. Together, these findings highlight the role of ferroptosis in MS-associated oligodendrocyte loss and position AKR1C1 as a potential therapeutic target for preserving oligodendrocyte integrity and supporting neuronal function in MS patients.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103463"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative stress promotes lipid-laden macrophage formation via CYP1B1","authors":"Yin Zhu ,&nbsp;Saugata Dutta ,&nbsp;Yohan Han ,&nbsp;Dooyoung Choi ,&nbsp;Francesca Polverino ,&nbsp;Caroline A. Owen ,&nbsp;Payaningal R. Somanath ,&nbsp;Xiaoyun Wang ,&nbsp;Duo Zhang","doi":"10.1016/j.redox.2024.103481","DOIUrl":"10.1016/j.redox.2024.103481","url":null,"abstract":"<div><div>Emerging evidence suggests that lipid-laden macrophages (LLM) participate in lung damage in various clinical conditions. However, the mechanisms involved in LLM formation are not fully understood. In this study, we aimed to investigate the link between reactive oxygen species (ROS) and LLM formation. We found that ROS triggered by cigarette smoke extract (CSE) or H₂O₂ significantly promoted LLM formation. Given the key role of ROS in LLM formation, we further demonstrated that LLM formation is induced by various ROS-producing stimuli, including bacteria, oxidized low-density lipoprotein (OxLDL), hyperoxia, and E-cigarette vapor extract (EVE). Meanwhile, cytochrome P450 family-1 subfamily B member 1 (CYP1B1) was highly upregulated in lung macrophages from chronic obstructive pulmonary disease (COPD) patients and CSE-treated macrophages. Functionally, CYP1B1 contributes to the CSE-induced lipid accumulation and LLM formation. CYP1B1 expression and LLM formation were effectively suppressed by antioxidant N-acetylcysteine (NAC) and carvedilol. The formation of LLM was also associated with classically activated M1 but not the M2 state. CSE-induced LLM showed time-dependent alterations in inflammatory response and phagocytic ability. In summary, our study highlights the role of oxidative stress in LLM formation. CYP1B1 contributes to ROS-induced LLM formation and may serve as a therapeutic target for reducing LLM-induced lung damage.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103481"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation of thiyl radicals in a spatiotemporal controlled manner by light: Applied for the cis to trans isomerization of unsaturated fatty acids/phospholipids","authors":"Biswajit Roy ,&nbsp;Ryota Kojima ,&nbsp;Obaed Shah ,&nbsp;Meg Shieh ,&nbsp;Eshani Das ,&nbsp;Shahrzad Ezzatpour ,&nbsp;Emiko Sato ,&nbsp;Yusuke Hirata ,&nbsp;Stephen Lindahl ,&nbsp;Atsushi Matsuzawa ,&nbsp;Hector C. Aguilar ,&nbsp;Ming Xian","doi":"10.1016/j.redox.2024.103475","DOIUrl":"10.1016/j.redox.2024.103475","url":null,"abstract":"<div><div>Thiyl radicals are important reactive sulfur species and can cause <em>cis</em> to <em>trans</em> isomerization on unsaturated fatty acids. However, biocompatible strategies for the controlled generation of thiyl radicals are still lacking. In this work, we report the study of a series of naphthacyl-derived thioethers as photo-triggered thiyl radical precursors. Tertiary naphthacyl thioether was identified to be a suitable template that could be used to produce both aryl and alkyl thiyl radicals under ultraviolet (UV) light or sunlight. The effective <em>cis</em>-to <em>trans</em>-isomerization of unsaturated fatty acid models (methyl oleate, methyl linoleate) and a natural phospholipid (cardiolipin) using these photo-triggered substrates was demonstrated. This reaction was also proved to proceed effectively in cells to produce thiyl radicals and subsequent fatty acid isomerization. Additionally, the most promising thiyl radical precursor showed antiviral activity in a pseudotyped virus model, likely due to disrupting viral lipid membranes upon UV activation. These findings highlight the potential of thiyl radicals for both biochemical and antiviral applications.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103475"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetylation of proximal cysteine-lysine pairs by alcohol metabolism","authors":"Courtney D. McGinnis,&nbsp;Peter S. Harris,&nbsp;Brenton I.M. Graham,&nbsp;John O. Marentette,&nbsp;Cole R. Michel,&nbsp;Laura M. Saba,&nbsp;Richard Reisdorph,&nbsp;James R. Roede,&nbsp;Kristofer S. Fritz","doi":"10.1016/j.redox.2024.103462","DOIUrl":"10.1016/j.redox.2024.103462","url":null,"abstract":"<div><div>Alcohol consumption induces hepatocyte damage through complex processes involving oxidative stress and disrupted metabolism. These factors alter proteomic and epigenetic marks, including alcohol-induced protein acetylation, which is a key post-translational modification (PTM) that regulates hepatic metabolism and is associated with the pathogenesis of alcohol-associated liver disease (ALD). Recent evidence suggests lysine acetylation occurs when a proximal cysteine residue is within ∼15 Å of a lysine residue, referred to as a cysteine-lysine (Cys-Lys) pair. Here, acetylation can occur through the transfer of an acetyl moiety via an S → N transfer reaction. Alcohol-mediated redox stress is known to occur coincidentally with lysine acetylation, yet the biochemical mechanisms related to cysteine and lysine crosstalk within ALD remain unexplored. A murine model of ALD was employed to quantify hepatic cysteine redox changes and lysine acetylation, revealing that alcohol metabolism significantly reduced the cysteine thiol proteome and increased protein acetylation. Interrogating both cysteine redox and lysine acetylation datasets, 1280 protein structures generated by AlphaFold2 represented by a 3D spatial matrix were used to quantify the distances between 557,815 cysteine and lysine residues. Our analysis revealed that alcohol metabolism induces redox changes and acetylation selectively on proximal Cys-Lys pairs with an odds ratio of 1.88 (p &lt; 0.0001). Key Cys-Lys redox signaling hubs were impacted in metabolic pathways associated with ALD, including lipid metabolism and the electron transport chain. Proximal Cys-Lys pairs exist as sets with four major motifs represented by the number of Cys and Lys residues that are pairing (Cys₁:Lys₁, Cys_x:Lys₁, Cys₁:Lys_x and Cys_x:Lys_x) each with a unique microenvironment. The motifs are composed of functionally relevant Cys-Ly altered within ALD, identifying potential therapeutic targets. Furthermore, these unique Cys-Lys redox signatures are translationally relevant as revealed by orthologous comparison with severe alcohol-associated hepatitis (SAH) explants, revealing numerous pathogenic thiol redox signals in these patients.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103462"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NCOA4 linked to endothelial cell ferritinophagy and ferroptosis:a key regulator aggravate aortic endothelial inflammation and atherosclerosis","authors":"Li Zhu ,&nbsp;Zijian Liu ,&nbsp;Jiahui Liu ,&nbsp;Zhenglong Li ,&nbsp;Youli Bao ,&nbsp;Xin Sun ,&nbsp;Wenchen Zhao ,&nbsp;An Zhou ,&nbsp;Hongfei Wu","doi":"10.1016/j.redox.2024.103465","DOIUrl":"10.1016/j.redox.2024.103465","url":null,"abstract":"<div><div>Atherosclerosis (AS) is associated with a high incidence of cardiovascular events, yet the mechanisms underlying this association remain unclear. Our previous study found that Atherosclerotic endothelial injury is closely associated with ferroptosis in ApoE^−/− mice. Ferroptosis is a novel mode of cell death induced by decreased antioxidant capacity of the organism and accumulation of reactive oxygen species. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy is an important regulator of sudden ferroptosis in cells. However, the role of NCOA4 in AS and the exact mechanism by which it regulates the ferritinophagy response remain unclear. Herein, we report that NCOA4 expression is elevated in ApoE^−/− mice and endothelial cells and is significantly correlated with AS. NCOA4 expression promoted ferroptosis, and was positively correlated with ferritinophagy response. Mechanistically, our findings indicate that LOX-1 is a key upstream target that influences the function of NCOA4. The specific pathway is related to the activation of cGAS-STING signaling to upregulate NCOA4 expression. Moreover, our findings demonstrate the \"Gualou-Xiebai\" herb pair can regulate LOX-1 to inhibit ferroptosis. Collectively, our results provide evidence of a connection between NCOA4-mediated promotion of AS and suggest that targeting upstream molecules regulating NCOA4 could be a potential therapy for AS.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103465"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer","authors":"Eeshrita Jog ,&nbsp;Ashwin Kumar Jainarayanan ,&nbsp;Alessandro La Ferlita ,&nbsp;Arnab Chakraborty ,&nbsp;Afiya Dalwai ,&nbsp;Showket Yahya ,&nbsp;Anusha Shivashankar ,&nbsp;Bhagya Shree Choudhary ,&nbsp;Aakash Chandramouli ,&nbsp;Mufaddal Kazi ,&nbsp;Darshan Jain ,&nbsp;Nileema Khapare ,&nbsp;Akshaya B ,&nbsp;Bushra K. Khan ,&nbsp;Poonam Gera ,&nbsp;Prachi Patil ,&nbsp;Rahul Thorat ,&nbsp;Nandini Verma ,&nbsp;Lalit Sehgal ,&nbsp;Avanish Saklani ,&nbsp;Nazia Chaudhary","doi":"10.1016/j.redox.2024.103458","DOIUrl":"10.1016/j.redox.2024.103458","url":null,"abstract":"<div><div>A significant clinical challenge in patients with colorectal cancer (CRC), which adversely impacts patient survival, is the development of therapy resistance leading to a relapse. Therapy resistance and relapse in CRC is associated with the formation of lipid droplets (LD) by stimulating de novo lipogenesis (DNL). However, the molecular mechanisms underlying the increase in DNL and the susceptibility to DNL-targeted therapies remain unclear. Our study demonstrates that colorectal drug-tolerant persister cells (DTPs) over-express Lipin1 (LPIN1), which facilitates the sequestration of free fatty acids into LDs. The increased expression is mediated by the ETS1-PTPN1-c-Src-CEBPβ pathway. Blocking the conversion of free fatty acids into LDs by treatment with statins or inhibiting lipin1 expression disrupts lipid homeostasis, leading to lipotoxicity and ferroptotic cell death in both DTPs and patient-derived organoids (PDOs) <em>in vitro</em>. Ferroptosis inhibitors or N-acetylcysteine (NAC) can alleviate lipid ROS and cell death resulting from lipin1 inhibition. This strategy also significantly reduces tumor growth in CRC DTP mouse xenograft and patient-derived xenograft (PDX) models. Our findings highlight a new metabolic vulnerability in CRC DTPs, PDO, and PDX models and provide a framework for the rational repurposing of statins. Targeting the phosphatidic acid (PA) to diacylglycerol (DAG) conversion to prevent lipid droplet formation could be an effective therapeutic approach for therapy-resistant CRC.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103458"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia","authors":"Hang Zhang ,&nbsp;Sheng Yang ,&nbsp;Yi-Lin Lu ,&nbsp;Luo-Qi Zhou ,&nbsp;Ming-Hao Dong ,&nbsp;Yun-Hui Chu ,&nbsp;Xiao-Wei Pang ,&nbsp;Lian Chen ,&nbsp;Lu-Lu Xu ,&nbsp;Lu-Yang Zhang ,&nbsp;Li-Fang Zhu ,&nbsp;Ting Xu ,&nbsp;Wei Wang ,&nbsp;Ke Shang ,&nbsp;Dai-Shi Tian ,&nbsp;Chuan Qin","doi":"10.1016/j.redox.2024.103473","DOIUrl":"10.1016/j.redox.2024.103473","url":null,"abstract":"<div><h3>Background</h3><div>Oxidative stress and microglial activation are critical pathomechanisms in ischemic white matter injury. Microglia, as resident immune cells in the brain, are the main cells undergoing oxidative stress response. However, the role and molecular mechanism of oxidative stress in microglia have not been clearly elucidated during white matter ischemia.</div></div><div><h3>Methods</h3><div>Extensive histological analysis of the corpus callosum was performed in BCAS mice at different time points to assess white matter injury, oxidative stress and microglial activation. Flow cytometric sorting and transcriptomic sequencing were combined to explore the underlying mechanisms regulating microglial oxidative stress and functional phenotypes. The expression of critical molecule in microglia was regulated using Cx3cr1^CreER mice and clinical-stage drugs to assess its effect on white matter injury and cognitive function.</div></div><div><h3>Results</h3><div>Our study identified nuclear factor erythroid-2 related factor 2 (Nrf2) as a key transcription factor regulating oxidative stress and functional phenotype in microglia. Interestingly, we found that the sustained decrease in transiently upregulated expression of Nrf2 following chronic cerebral hypoperfusion resulted in abnormal microglial activation and white matter injury. In addition, high loads of myelin debris promoted lipid peroxidation and ferroptosis in microglia with diminished antioxidant function. Microglia with pharmacologically or genetically stimulated Nrf2 expression exhibited enhanced resistance to ferroptosis and pro-regenerative properties to myelination due to lipid and iron metabolism reprogramming.</div></div><div><h3>Conclusion</h3><div>Weakened Nrf2-mediated antioxidant responses in microglia induced metabolic disturbances and ferroptosis during chronic cerebral hypoperfusion. Targeted enhancement of Nrf2 expression in microglia may be a potential therapeutic strategy for ischemic white matter injury.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103473"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11728325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage metabolic reprogramming ameliorates diabetes-induced microvascular dysfunction","authors":"Qiu-Yang Zhang ,&nbsp;Hui-Ying Zhang ,&nbsp;Si-Guo Feng ,&nbsp;Mu-Di Yao ,&nbsp;Jing-Juan Ding ,&nbsp;Xiu-Miao Li ,&nbsp;Rong Ye ,&nbsp;Qing Liu ,&nbsp;Jin Yao ,&nbsp;Biao Yan","doi":"10.1016/j.redox.2024.103449","DOIUrl":"10.1016/j.redox.2024.103449","url":null,"abstract":"<div><div>Macrophages play an important role in the development of vascular diseases, with their homeostasis closely linked to metabolic reprogramming. This study aims to explore the role of circular RNA-mediated epigenetic remodeling in maintaining macrophage homeostasis during diabetes-induced microvascular dysfunction. We identified a circular RNA, circRNA-sperm antigen with calponin homology and coiled-coil domains 1 (cSPECC1), which is significantly up-regulated in diabetic retinas and in macrophages under diabetic stress. cSPECC1 knockdown in macrophages attenuates M1 macrophage polarization and disrupts macrophage-endothelial crosstalk <em>in vitro</em>. cSPECC1 knockdown in macrophages mitigates diabetes-induced retinal inflammation and ameliorates retinal vascular dysfunction. Mechanistically, cSPECC1 regulates GPX2 expression by recruiting eIF4A3, enhancing GPX2 mRNA stability and altering arachidonic acid metabolism. The metabolic intermediate 12-HETE has emerged as a key mediator, regulating both macrophage homeostasis and the crosstalk between macrophages and endothelial cells. Exogenous 12-HETE supplementation interrupts the anti-angiogenic effects of cSPECC1 knockdown. Collectively, circSPECC1 emerges as a novel regulator of macrophage-mediated vascular integrity and inflammation. Targeting the metabolic reprogramming of macrophages presents a promising therapeutic strategy for mitigating diabetes-induced vascular dysfunction.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"79 ","pages":"Article 103449"},"PeriodicalIF":10.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}