Redox Biology最新文献

{"title":"Neutrophil extracellular traps exacerbate inflammatory arthritis by inhibiting γδ Treg cell differentiation via the AIM2 inflammasome","authors":"Yipeng Zeng ,&nbsp;Jiajie Lin ,&nbsp;Zipeng Xiao ,&nbsp;Zhikun Li ,&nbsp;Guan Zheng ,&nbsp;Yi Zhou ,&nbsp;Qibo Li ,&nbsp;Chenying Zeng ,&nbsp;Zepeng Su ,&nbsp;Wenhui Yu ,&nbsp;Zhongyu Xie","doi":"10.1016/j.redox.2025.103881","DOIUrl":"10.1016/j.redox.2025.103881","url":null,"abstract":"<div><div>Inflammatory arthritis is a set of systemic autoimmune diseases that lead to joint destruction. Recent findings suggest that γδ T cell dysfunction plays a crucial role in the development of inflammatory arthritis, but its underlying mechanisms remain elusive. In this study, we demonstrated that neutrophil extracellular trap (NET) levels were elevated in inflammatory arthritis patients and collagen-induced arthritis (CIA) model mice, which inhibited γδ Treg cell differentiation and contributed to the decreased proportion of γδ Treg cells in these patients and model mice. Inhibition of NET formation with sivelestat (SVT) and CI-amidine restored the proportion of γδ Treg cells and had a therapeutic effect on CIA model mice. In terms of mechanism, the endocytosed NET-associated DNA components bound to an intracellular DNA sensor AIM2, promoting the AIM2 inflammasome activation and the subsequent gasdermin D-mediated mitochondrial dysfunction. This process led to the pathological accumulation of reactive oxygen species, therefore directly inhibiting γδ Treg cell differentiation. Our study reveals the detailed mechanism through which NETs impeded γδ Treg cell differentiation and then exacerbated inflammatory arthritis, suggesting an underlying therapeutic strategy for inflammatory arthritis by targeting the NET-γδ Treg cell axis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"Article 103881"},"PeriodicalIF":11.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145227430","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":"PARK7-driven IGF2BP3–K76 lactylation mediates ferroptosis and HAIC resistance in hepatocellular carcinoma","authors":"Zhiwen Zhu ,&nbsp;Xinyu Xia ,&nbsp;Yuanxiang Lu ,&nbsp;Danfeng Li ,&nbsp;Xincheng He ,&nbsp;Baohua Zhang ,&nbsp;Ge Xiong ,&nbsp;Wanguang Zhang ,&nbsp;Huifang Liang ,&nbsp;Hong Zhu","doi":"10.1016/j.redox.2025.103869","DOIUrl":"10.1016/j.redox.2025.103869","url":null,"abstract":"<div><div>Oxaliplatin/5-fluorouracil (OXA/5-FU)-based hepatic artery infusion chemotherapy (HAIC) represents a promising strategy against advanced hepatocellular carcinoma (HCC), yet acquired resistance frequently impedes its efficacy. Here, we identify lactylation of IGF2BP3 at lysine 76 (IGF2BP3–K76lac) as a key driver of HAIC resistance. IGF2BP3–K76lac overexpression enhances chemoresistance in vitro and in vivo. Mechanistically, lactylation at IGF2BP3 K76 strengthens its affinity for m6A-modified FSP1 mRNA, upregulating FSP1 and conferring ferroptosis resistance. Blocking of IGF2BP3–K76lac bolsters OXA/5-FU-induced ferroptosis, disrupts antioxidant defenses, and curbs tumor growth. Moreover, PARK7 functions as a lactyltransferase to facilitate IGF2BP3–K76lac via increasing the binding of lactate at IGF2BP3–K76 site. Finally, blocking antibody targeting IGF2BP3–K76lac was shown to work synergistically with OXA/5-FU to restore chemosensitivity. Taken together, our findings reveal a critical role for the PARK7–IGF2BP3–K76lac–FSP1 axis in HAIC resistance, highlighting IGF2BP3–K76lac as a potential therapeutic target in HCC.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"Article 103869"},"PeriodicalIF":11.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209266","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":"NFS1, together with FXN, protects cells from ferroptosis and DNA damage in diffuse large B-cell lymphoma","authors":"Xue Shi ,&nbsp;Yun Zhao ,&nbsp;Hong-Yu Gao ,&nbsp;Wei Yang ,&nbsp;Jun Liao ,&nbsp;Hui-Han Wang ,&nbsp;Xiao-Tian Wang ,&nbsp;Wei Yan","doi":"10.1016/j.redox.2025.103878","DOIUrl":"10.1016/j.redox.2025.103878","url":null,"abstract":"<div><div>Diffuse large B cell lymphoma (DLBCL) is a common hematologic malignancy. NFS1 cysteine desulfurase, as a rate-limiting enzyme in the iron-sulfur cluster (ISC) biogenesis, has been reported to be associated with tumor progression. However, the role of NFS1 in DLBCL remains elusive. Here, we showed an upregulation of NFS1 in DLBCL tumor tissues. Knockdown of NFS1 decreased the cell viability and enhanced LDH levels in DLBCL cells. Animal experiments further indicated that downregulation of NFS1 suppresses tumor growth in vivo. NFS1 knockdown increased the lipid reactive oxygen species (ROS) level in cells, and this promotional effect was reversed by ferroptosis inhibitors, but not influenced by other types of cell death inhibitors. This result suggested that NFS1 depletion-impaired cell viability is associated with ferroptosis. Silenced NFS1 aggravated ferroptosis inducers caused cell viability inhibition, lactate dehydrogenase (LDH), and lipid ROS levels enhancement, while the addition of ferroptosis inhibitors abated these trends. Moreover, catalytic residue mutation of NFS1 did not affect its protein expression but decreased the cell viability, which was promoted by NFS1 upregulation, indicating that the protective effect of NFS1 in DLBCL cells was related to its catalytic activity. Further results showed that frataxin (FXN), the upstream activator of NFS1, reduced the cell viability in NFS1 upregulated cells. Consistent with NFS1, FXN silencing aggravated erastin-induced cell viability inhibition and LDH level enhancement. Silencing NFS1 or FXN inhibited the level of iron ions storage-related proteins but promoted the level of transport-related proteins. In addition, silenced NFS1 or FXN displayed an inhibition effect on protein expression of DNA polymerases, but a promotion trend in the phosphorylation of DNA damage markers. In conclusion, we demonstrated that ISC-related proteins NFS1 and FXN protect DLBCL cells from ferroptosis and DNA damage, thus exhibiting an essential role in DLBCL progression.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"Article 103878"},"PeriodicalIF":11.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153414","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":"Glypican 1 mechanosensing mediates eNOS uncoupling during hydrostatic pulmonary edema","authors":"Lakshmi Narasimha Rao Thota ,&nbsp;Joaquin Enrique Lopez Rosales ,&nbsp;Ayman Isbatan ,&nbsp;Christian Bime ,&nbsp;Joao Luis Carvalho-de-Souza ,&nbsp;Randal O. Dull ,&nbsp;Stephen M. Black ,&nbsp;Andreia Zago Chignalia","doi":"10.1016/j.redox.2025.103876","DOIUrl":"10.1016/j.redox.2025.103876","url":null,"abstract":"<div><div>Hydrostatic pulmonary edema is a life-threatening condition caused by an acute increase in pulmonary capillary pressure. The molecular mechanisms whereby hydrostatic pulmonary edema develops are unresolved. The pulmonary endothelial glycocalyx is a mechano-sensitive signaling layer known to regulate lung endothelial permeability. Within the glycocalyx, membrane-bound heparan sulfate proteoglycans (HSPGs) are putative mechano-sensors. Herein, we investigated if the membrane-bound HSPG glypican 1 is a mechanosensor in the lung vasculature and its role in hydrostatic pulmonary edema progression. Using an isolated perfused lung system, we showed that glypican 1 knockout mice (<em>Gpc1</em>^{<em>−/−</em>}) are protected from pressure-induced lung edema, a phenotype associated with impaired 70 KDa dextran transport and decreased reactive oxygen species (ROS) production. Using wild-type (WT) mouse lung endothelial cells (MLEC) and human lung microvascular endothelial cells (HLMEC), we show that high pressure induces the activation of Protein Kinase C-alpha (PKCα) at Y⁶⁵⁷, which phosphorylates endothelial nitric oxide synthase (eNOS) at T⁴⁹⁵. This is associated with increased ROS production by eNOS-dependent pathways. The inhibition of eNOS with ethyl thiourea (ETU) or N5-(1-iminoethyl)-<span>l</span>-ornithine (L-NIO) mitigates the effects of high pressure on ROS production, lung edema, and barrier stability. This pathologic signaling axis is not activated in <em>Gpc1</em>^{<em>−/−</em>} MLEC exposed to high-pressure conditions. Notably, cells deficient in Glypican 1 show increased phosphorylation of PKCα at T⁶³⁸, a site associated with PKCα stability and inactivation. The protective signaling mechanisms observed in <em>Gpc1</em>^{<em>−/−</em>} MLEC are replicated in HLMEC silenced for glypican 1, supporting a conserved role for glypican 1 in barrier function across species. In conclusion, we show that glypican 1 is a mechanosensor in the lung vasculature that mediates the effects of high pressure on barrier function by redox-sensitive pathways. This may be important for the progression of hydrostatic pulmonary edema in humans. Therapies targeting glypican 1 may be novel strategies to treat hydrostatic pulmonary edema.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"Article 103876"},"PeriodicalIF":11.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145159551","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":"Synthetic anticoagulant octaparin targets mitochondrial cardiolipin-GSDMD axis to rescue redox homeostasis in sepsis","authors":"Shule Zhang ,&nbsp;Cong Feng ,&nbsp;Ning Yu ,&nbsp;Rui Fang ,&nbsp;Yingxin Zhang ,&nbsp;Simeng Chen ,&nbsp;Lijuan Cao ,&nbsp;Jianfa Zhang","doi":"10.1016/j.redox.2025.103877","DOIUrl":"10.1016/j.redox.2025.103877","url":null,"abstract":"<div><div>Sepsis, characterized by dysregulated immune responses and mitochondrial dysfunction, currently has few effective therapies that directly target these cellular mechanisms, and conventional heparin and related analogues provide inadequate immunomodulatory benefits. Here, we investigated the synthetic heparin analogue octaparin, which exhibits enhanced anticoagulant safety, for its potential to mitigate sepsis by targeting mitochondrial and redox pathways. Using murine models of lipopolysaccharide (LPS)-induced endotoxemia and <em>Salmonella typhimurium</em>-induced sepsis, along with in vitro studies performed using murine bone marrow-derived macrophages (BMDMs) and the human acute monocytic leukemia THP-1 cell line, we demonstrate that octaparin significantly improves survival and attenuates multi-organ (lung, liver, kidney) damage. Octaparin outperformed heparin, enoxaparin, and fondaparinux in suppressing systemic inflammation including TNF-α, IL-6, IL-1β and bacterial burden. Transcriptomic analysis revealed octaparin reprograms macrophage immunometabolism, suppressing pro-inflammatory pathways while enhancing phagocytosis. Crucially, octaparin inhibited both canonical and non-canonical inflammasome activation, reduced generation of the pyroptotic executor GSDMD-N-terminal fragment (GSDMD-NT), and specifically diminished mitochondrial localization of GSDMD-NT by downregulating key cardiolipin synthesis and transport genes. Furthermore, octaparin uniquely reversed LPS-induced mitochondrial dysfunction. This restoration was accompanied by improvements in mitochondrial quality and the reestablishment of redox homeostasis. Collectively, octaparin confers multifaceted protection in sepsis, positioning it as a promising redox-targeted therapeutic for sepsis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"Article 103877"},"PeriodicalIF":11.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119632","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":"Role of mitochondria transmission in ischemic stroke: Friend or foe?","authors":"Lan Yang ,&nbsp;Xuan Wei ,&nbsp;Zi Liao ,&nbsp;Bei Chen ,&nbsp;Guang Zeng ,&nbsp;Zhigang Mei","doi":"10.1016/j.redox.2025.103868","DOIUrl":"10.1016/j.redox.2025.103868","url":null,"abstract":"<div><div>Ischemic stroke ranks as the second leading cause of mortality and the third disability worldwide. Disruption of energy metabolism and subsequent inflammation driven by oxidative stress constitute significant barriers to functional recovery. Proper distribution and function preservation of mitochondria are essential for maintaining energy homeostasis and modulating the inflammatory response during cerebral ischemia and reperfusion injury. Accumulating evidence indicates that both dysfunctional mitochondrial fragments and functional mitochondria undergo intracellular and intercellular transmission, significantly influencing stroke outcomes. The review details two contrasting mitochondrial processes in ischemic stroke: the release of dysfunctional mitochondrial fragments into the cytoplasm or extracellular space and the entry of functional mitochondria into damaged cells, which plays a dual role: friend or foe. The release of dysfunctional fragments activates downstream pattern recognition receptors, including the cyclic GMP-AMP synthase–stimulator of interferon genes pathway, NLR family pyrin domain containing 3/absent in melanoma 2 inflammasome, and Toll-like receptors, triggering inflammatory cascades within the neurovascular unit and initiating cell death pathways contributing to cerebral injury. In contrast, the transfer of functional mitochondria plays a protective role by attenuating oxidative stress, preserving mitochondrial quality control, restoring neuronal energy metabolism, inhibiting apoptosis, and maintaining blood-brain barrier integrity. Therapeutic approaches that inhibit the release of dysfunctional mitochondrial fragments, enhance functional mitochondria transfer, or apply mitochondrial transplantation offer significant potential for improving outcomes in ischemic stroke.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"Article 103868"},"PeriodicalIF":11.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119677","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":"nNOS-mediated S-nitrosylation of TCOF1 regulates KRAS proteostasis to suppress hepatoblastoma progression.","authors":"Meng Wang, Yupeng Wang, Yue Qian, Ziyan Luo, Siqi Dong, Zhuoyan Li, Lingling Wu, Fang Yu, Zihua Lin, Lin Qiu, Hua Jiang, Linna Yu","doi":"10.1016/j.redox.2025.103870","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103870","url":null,"abstract":"<p><p>Neuronal nitric oxide synthase (nNOS) plays dual roles in tumorigenesis, but its function in hepatoblastoma (HB) remains unclear. Analysis of 30 clinical HB samples reveals significant nNOS downregulation, correlating with tumor malignancy. Overexpression of nNOS inhibits HB cell proliferation and tumor growth in vitro and in vivo. Multi-omics analysis identifies the MAPK pathway as a key target, with KRAS protein levels most prominently reduced. Mechanistically, nNOS induces S-nitrosylation of TCOF1 at cysteine 644, disrupting TCOF1-KRAS interaction and thereby accelerating KRAS protein degradation. These findings establish the nNOS-TCOF1-KRAS axis as a critical regulator of HB progression and propose a novel NO-based therapeutic strategy for KRAS-driven cancers.</p>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"103870"},"PeriodicalIF":11.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308936","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":"Sigma-1 receptor counteracts non-cell-autonomous poly-PR-induced astrocytic oxidative stress in C9orf72 ALS","authors":"Hsuan‐Cheng Wu ,&nbsp;Teng-Wei Huang ,&nbsp;Eddie Feng‐Ju Weng ,&nbsp;Chun-Yu Lin ,&nbsp;Tsung‐Ping Su ,&nbsp;Hsiang‐En Wu ,&nbsp;Shao‐Ming Wang","doi":"10.1016/j.redox.2025.103875","DOIUrl":"10.1016/j.redox.2025.103875","url":null,"abstract":"<div><div><em>C9orf72</em>-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by the accumulation of toxic dipeptide repeat proteins (DPRs) generated from G₄C₂ hexanucleotide repeat expansions. Among these, the arginine-rich poly-PR (proline-arginine) species is the most neurotoxic, eliciting glial activation and neuroinflammation via non-cell-autonomous mechanisms. Although growing evidence implicates glial cells, particularly astrocytes, in disease progression, the molecular pathways linking neuron-derived poly-PR to astrocyte-mediated oxidative stress remain poorly understood. We demonstrate that exogenous poly-PR induces robust NOX4 expression and hydrogen peroxide (H₂O₂) production in astrocytes through activation of the IKK/IκB/NF-κB p65 signaling pathway. Mechanistically, poly-PR promotes nuclear translocation of p65 and enhances its binding to the NOX4 promoter, thereby amplifying astrocytic oxidative stress. Overexpression of the Sigma-1 receptor (Sigma-1R), an endoplasmic reticulum-resident chaperone, significantly attenuates poly-PR-induced NOX4 transcription and reactive oxygen species (ROS) production by interacting with p65 and blocking its nuclear translocation, independently of upstream p65 phosphorylation. Notably, clemastine, a clinically approved Sigma-1R agonist, suppresses astrocytic NOX4 expression by disrupting p65 binding to the NOX4 promoter. In a mouse model of <em>C9orf72</em> ALS, Sigma-1R deficiency exacerbates poly-PR-induced neurodegeneration, astrogliosis, and NOX4 upregulation, whereas Sigma-1R sufficiency confers neuroprotection and anti-inflammatory effects. This study identifies Sigma-1R as a critical modulator of non-cell-autonomous poly-PR toxicity and establishes its activation as a potent suppressor of astrocyte-derived oxidative stress. Our findings uncover a previously unrecognized glial mechanism driving <em>C9orf72</em> ALS pathogenesis and support Sigma-1R activation, via clemastine, as a promising therapeutic strategy to mitigate neuroinflammation and disease progression.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"Article 103875"},"PeriodicalIF":11.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119678","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":"γ-Tocotrienol attenuates oxidative stress and preserves mitochondrial function in inflammation-induced muscle atrophy","authors":"Jun Yi Chong ,&nbsp;Tsui-Chin Huang ,&nbsp;Sheng-Ming Chueh ,&nbsp;Cheng-Yi Ma ,&nbsp;Tzu-Ting Kuo ,&nbsp;Jia-Jun He ,&nbsp;Yii-Jwu Lo ,&nbsp;Kuan-Chieh Peng ,&nbsp;Mohamed Ali ,&nbsp;Hsin-Yi Chang ,&nbsp;Shih-Min Hsia","doi":"10.1016/j.redox.2025.103874","DOIUrl":"10.1016/j.redox.2025.103874","url":null,"abstract":"<div><div>Muscle atrophy, marked by the loss of skeletal muscle mass and strength, presents a major health concern with diverse etiologies, including chronic inflammation. Effective interventions are urgently needed for its prevention and treatment. Although α-tocopherol, the most abundant form of vitamin E, is known for its antioxidant benefits in muscle health, γ-tocotrienol exhibits superior antioxidant and anti-inflammatory properties. This study investigates the protective effects of γ-tocotrienol against muscle atrophy and compares its efficacy with α-tocopherol. Muscle atrophy was induced in differentiated C2C12 myotubes using lipopolysaccharide (LPS), with vitamin E pre-treatment applied prior to LPS challenge. Myotube morphology, expression of atrophy-related markers, and underlying molecular pathways were examined through immunofluorescence, western blotting, and quantitative proteomics. LPS treatment induced significant myotube atrophy without affecting cell viability. Notably, γ-tocotrienol pre-treatment preserved myotube size and suppressed key atrophy markers, including the E3 ubiquitin ligases MuRF-1 and Fbxo32/Atrogin-1. Proteomic analysis quantified 5,371 proteins and revealed that γ-tocotrienol alleviated atrophy by enhancing extracellular matrix organization and attenuating oxidative stress and mitochondrial dysfunction. These protective effects were further confirmed <em>in vivo</em>, where γ-tocotrienol administration preserved muscle strength, suppressed pro-inflammatory signaling, and restored mitochondrial biogenesis in LPS-treated mice. Collectively, these findings demonstrate that γ-tocotrienol offers superior protection against muscle atrophy compared to α-tocopherol, highlighting its therapeutic potential for individuals at risk of muscle wasting.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"Article 103874"},"PeriodicalIF":11.9,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153412","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":"Copper overload worsens the inflammatory response of microglia to amyloid beta (Aβ) by impairing phagocytosis and promoting mitochondrial DNA-mediated NLRP3 inflammasome activation","authors":"Marlene Zubillaga ,&nbsp;Xenia Abadin ,&nbsp;Elia Ivars ,&nbsp;Margalida Puigròs ,&nbsp;Ramon Trullas ,&nbsp;M. José Bellini ,&nbsp;Nathalie Arnal ,&nbsp;Anna Colell","doi":"10.1016/j.redox.2025.103872","DOIUrl":"10.1016/j.redox.2025.103872","url":null,"abstract":"<div><div>Microglia play a significant role in the development and progression of Alzheimer's disease (AD). These brain-resident immune cells efficiently clear neurotoxic amyloid beta (Aβ) peptides; however, chronic activation may overwhelm their protective abilities, resulting in persistent neuroinflammation. The causes of aberrant microglial activation in AD remain elusive. Emerging evidence indicates that copper (Cu) accumulation, which can arise from prolonged exposure to various environmental sources, modifies the innate immune response in AD. Here, we sought to explore the mechanisms by which Cu overload regulates the microglial phenotype when exposed to Aβ. Our findings showed that exposure to sublethal doses of Cu led to the accumulation of this transition metal in the mitochondria. Elevated mitochondrial Cu (mtCu) levels were accompanied by reduced mitochondrial glutathione (mtGSH) and high oxidative stress, leading to Aβ-induced inflammasome activation through the release of oxidized mitochondrial DNA (ox-mtDNA). Moreover, increased intracellular Cu levels enhanced cholesterol biosynthesis and facilitated its transport to mitochondria. The combination of elevated cholesterol and mitochondrial oxidative stress hindered the ability of microglia to phagocytose Aβ effectively. As expected, conditioned medium from Cu-activated microglia reduced neuronal viability. The neurotoxicity caused by Cu-overloaded microglia was prevented by inhibiting inflammasome activation and restoring mtGSH levels. In conclusion, our study outlines a mechanistic pathway by which chronic exposure to environmental Cu may lead to neuroinflammation and Aβ accumulation in AD, underscoring the crucial role of mitochondrial oxidative stress.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"87 ","pages":"Article 103872"},"PeriodicalIF":11.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119631","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}