Redox Report最新文献

{"title":"γ-Glutamylcysteine alleviates hypertension and vascular remodeling in SHR by suppressing oxidative stress through Keap1 S-glutathionylation.","authors":"Jianzhen Lei, Yueru Kong, Chao Ye, Chuanyue Zhang, Yi Shen, Xin Wu, Qiuyue Wu, Ying Han, Min Chen, Yueqi Song, Qing Yan, Fen Zheng, Xinyi Xia","doi":"10.1080/13510002.2026.2734676","DOIUrl":"10.1080/13510002.2026.2734676","url":null,"abstract":"<p><strong>Objectives: </strong>Pathological arterial remodeling heavily depends on the aberrant proliferation and migration of vascular smooth muscle cells (VSMCs). This study explores how <i>γ</i>-Glutamylcysteine (<i>γ</i>-GC) regulates VSMC signaling to mitigate hypertensive structural damage.</p><p><strong>Methods: </strong>Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats received intraperitoneal injections of <i>γ</i>-GC (100 mg/kg) every two days for 4 weeks. Blood pressure and arterial remodeling were evaluated. Primary aortic VSMCs were cultured for cellular mechanism analysis. To verify Nrf2 pathway requirement, the Nrf2 inhibitor ML385 was applied <i>in vitro</i> and via osmotic pumps <i>in vivo</i>.</p><p><strong>Results: </strong><i>γ</i>-GC lowered systemic blood pressure and prevented arterial medial thickening in SHR, while normotensive controls remained unaffected. In SHR-VSMCs, <i>γ</i>-GC inhibited cell migration, proliferation, and phenotypic switching, and alleviated cellular oxidative stress. RNA-seq revealed significant enrichment of the Nrf2 signaling pathway. Mechanistically, <i>γ</i>-GC induced Keap1 S-glutathionylation, which disrupted the Keap1 and Nrf2 interaction and promoted Nrf2 nuclear translocation. Notably, Nrf2 inhibition with ML385 abolished the protective effects of <i>γ</i>-GC <i>in vivo</i> and <i>in vitro</i>.</p><p><strong>Discussion: </strong><i>γ</i>-GC attenuates hypertensive arterial remodeling by modulating intracellular signaling, specifically through Keap1 S-glutathionylation-dependent Nrf2 activation. The Keap1/Nrf2 signaling axis is required for <i>γ</i>-GC to restore VSMC function, suggesting a targeted molecular mechanism for cardiovascular protection.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"31 1","pages":"2734676"},"PeriodicalIF":6.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13600300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ovalbumin oxidative modification fingerprints depend on gas plasma-driven reactive species profiles.","authors":"Paul Schulan, Kristian Wende, Ramona Clemen, Torsten Gerling, Klaus-Dieter Weltmann, Klaus Ruhnau, Thomas von Woedtke, Michael Lalk, Sander Bekeschus","doi":"10.1080/13510002.2026.2688623","DOIUrl":"10.1080/13510002.2026.2688623","url":null,"abstract":"<p><strong>Objective: </strong>Oxidative protein modifications have been linked to several diseases, but the variety and diversity of modifications are less studied.</p><p><strong>Methods: </strong>We used the chicken egg protein ovalbumin and gas plasma technology, a potent source of various reactive species, for protein oxidation. Using high-resolution mass spectrometry and an in-house workflow, over 80 distinct oxidative protein modifications were mapped at per-amino-acid resolution. To examine how modification profiles depend on changes in reactive species types and concentrations, we generated 12 distinct argon gas plasmas by systematically varying molecular gas admixtures (water, ethanol, oxygen, and nitrogen).</p><p><strong>Results: </strong>Optical emission spectroscopy (OES) and photometric determination of deposited long-lived species (hydrogen peroxide, nitrite, and nitrate) were applied to profile gas plasma conditions, revealing the admixture-dependent impact on the reactive oxygen/nitrogen species (ROS/RNS) fingerprint. Correlation analysis with mass spectrometry data revealed the significant involvement of atomic oxygen and hydrogen peroxide in protein oxidation. The enrichment of specific reactive species created by a defined gas plasma composition generated specific ovalbumin oxidation profiles resolved per amino acid. Feed gas-dependent oxidation hotspots, such as Trp149 for dry argon gas or Met274 for hydroxyl radical-rich humidified argon gas, were identified.</p><p><strong>Discussion: </strong>This first-of-its-kind study reveals intricate relationships between dynamic reactive species environments and protein oxidation profiles using ovalbumin as a model system.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"31 1","pages":"2688623"},"PeriodicalIF":6.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13276820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The oxidative stress paradigm in arbovirus infections: mechanisms and therapeutic insights.","authors":"Chang Ke Yee, Rafidah Lani, Pouya Hassandarvish","doi":"10.1080/13510002.2026.2659994","DOIUrl":"10.1080/13510002.2026.2659994","url":null,"abstract":"<p><strong>Background: </strong>Arbovirus infections impose a substantial global health burden, further complicated by their ability to induce oxidative stress through excessive generation of reactive oxygen species (ROS). This oxidative stress triggers a cascade that enhances viral replication and dysregulates immune responses, ultimately exacerbating disease pathology.</p><p><strong>Objective: </strong>In this review, we delineate the molecular pathways through which arbovirus-induced ROS activate NF-κB signalling, impair mitochondrial function, and alter the expression of key antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase), culminating in inflammatory tissue damage.</p><p><strong>Discussions: </strong><i>In vitro</i> studies demonstrate that various alkaloids and polyphenols reduce viral load, while N-acetylcysteine has shown the ability to attenuate inflammation and reduce viral titres across both <i>in vitro</i> and <i>in vivo</i> models. Despite these advances, translation to clinical practice is constrained by limited compound bioavailability, variable pharmacokinetics, optimal timing windows, and a lack of standardized redox assays.</p><p><strong>Conclusion: </strong>We propose that targeted redox-modulating strategies, such as integrating genomic and metabolomic profiling, activating Nrf2 pathways, and incorporating advanced imaging techniques, warrant systematic evaluation using rigorous <i>in vivo</i> models and clinical trials. Defining optimal redox-directed interventions has the potential to catalyse the discovery of novel therapeutics that disrupt pro-viral oxidative pathways and improve outcomes in arboviral disease.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"31 1","pages":"2659994"},"PeriodicalIF":6.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147692201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enzymatic and non-enzymatic oxidation of fibrillar collagen.","authors":"Felipe Caliani Mathias-Netto, Nathalia Margarida Cantuária, Renato Simões Gaspar","doi":"10.1080/13510002.2026.2682046","DOIUrl":"10.1080/13510002.2026.2682046","url":null,"abstract":"<p><strong>Objectives: </strong>Collagen is a long-lived protein present in the extracellular matrix of force-bearing tissues. It has a unique amino acid composition of predominantly glycine, proline and hydroxyproline that repeats throughout its characteristic triple helical structure. In the extracellular space, collagen interact first by a non-enzymatic, entropy-driven process given their high hydrophobicity. Then, enzymes, such as lysyl oxidase (LOX), create covalent bonds (i.e. crosslinks) between triple helices, generating reactive oxygen species (ROS) as a byproduct. Moreover, it was recently discovered that collagen itself generates ROS upon stretching. Therefore, given the close proximity of ROS-generating sources, it seems plausible that collagen undergoes non-enzymatic oxidation.</p><p><strong>Methods: </strong>This review discusses collagen structure, mechanisms of crosslink formation and collagen oxidation.</p><p><strong>Results: </strong>Despite abundant data on the mechanisms of LOX-mediated collagen oxidation, there is sparse data on the effects of non-enzymatic oxidation on collagen chemical and biophysical properties, as well as its effects on cells and tissues.</p><p><strong>Discussion: </strong>The premise that collagen oxidation could lead to persistent damage is discussed in light of the immunogenicity and proteolysis induced by such modifications. Overall, data support that oxidative modifications in collagen should be further explored and could pose as a novel underlying mechanism in ageing and chronic diseases.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"31 1","pages":"2682046"},"PeriodicalIF":6.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13262103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148219499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis inhibition and mitochondrial rescue: a novel mechanism of emodin in rheumatoid arthritis.","authors":"Linlan Zhou, Jun Liu, Jing Ren, Dehao Du, Xiaofeng Rong","doi":"10.1080/13510002.2026.2646383","DOIUrl":"10.1080/13510002.2026.2646383","url":null,"abstract":"<p><strong>Objectives: </strong>Rheumatoid arthritis (RA) is characterized by chronic synovitis and progressive joint destruction. Ferroptosis has been implicated in RA pathogenesis through synovial iron accumulation and oxidative stress. Glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) are key regulators of ferroptosis, but their specific roles in RA remain incompletely defined. The objective of this research was to explore the therapeutic effects and the mechanisms behind emodin (EMO) in RA.</p><p><strong>Methods: </strong>The therapeutic efficacy and mechanisms of EMO were evaluated in collagen-induced arthritis mice and lipopolysaccharide-stimulated RAW264.7 macrophages. Joint pathology, inflammation, oxidative stress, ferroptosis, and mitochondrial function were analyzed using histology, micro-computed tomography, western blotting, immunohistochemistry, and microscopy. Key targets were identified and validated using molecular dynamics, molecular docking, proteomics, and network pharmacology.</p><p><strong>Results: </strong>EMO alleviated joint inflammation and bone destruction, reduced pro-inflammatory cytokines and oxidative stress, restored iron and mitochondrial homeostasis, and inhibited ferroptosis. Mechanistically, EMO inhibited ferroptosis through the GPX4/ACSL4 axis, as evidenced by increased GPX4 and decreased ACSL4 expression.</p><p><strong>Conclusions: </strong>EMO ameliorates experimental arthritis mainly by suppressing ferroptosis via the GPX4/ACSL4 axis, highlighting ferroptosis as a previously underappreciated therapeutic target in RA and supporting EMO as a potential adjunctive treatment for RA.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"31 1","pages":"2646383"},"PeriodicalIF":6.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147499731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NOX2/NOX4-associated oxidative stress contributes to G6PD-associated metabolic remodeling and ferroptosis during mice luteolysis.","authors":"Fei Li, JiaHao Song, Wei Zou, Yulu Zhang, YanMin Cheng, HongRu Zhao, Bei Yang, Haibin Kuang","doi":"10.1080/13510002.2026.2724653","DOIUrl":"10.1080/13510002.2026.2724653","url":null,"abstract":"<p><strong>Objective: </strong>Ferroptosis has been shown to participate in luteolysis, yet the upstream signals and metabolic remodeling that trigger it remain unknown. This study aims to clarify these mechanisms.</p><p><strong>Methods: </strong>Physiological postpartum and PGF2α-induced luteolysis models were established in mice. Targeted energy metabolomics, pharmacological inhibition and adenoviral shRNA-mediated knockdown were employed in vivo and in primary luteal cells to measure ferroptosis markers, G6PD activity, NADP⁺/NADPH ratio and NOX2/NOX4 expression.</p><p><strong>Results: </strong>In both models, luteal regression was accompanied by increased ACSL4, decreased GPx4 and GSH, and elevated Fe²⁺ and lipid peroxidation and NOX2 and NOX4 expression. Metabolic analysis revealed 6-phosphogluconate accumulation, reduced pyruvate and pyruvate kinase M activity, and increased G6PD expression and activity, but NADPH depletion and redox imbalance. <i>In vivo</i>, combined NOX2/NOX4 knockdown reduced ROS accumulation, suppressed G6PD hyperactivation, alleviated ferroptotic injuryand delayed regression Moreover, G6PD inhibition with 6-AN similarly reduced oxidative stress and ferroptosis and partially restored progesterone secretion. In primary luteal cells, G6PD knockdown or 6-AN treatment attenuated PGF2α-induced ferroptosis and improved cell viability. Simultaneously, NOX2/NOX4 silencing, N-acetylcysteine, or Ferrostatin-1 suppressed PGF2α-induced G6PD activation, and attenuated oxidative stress and ferroptosis.</p><p><strong>Conclusion: </strong>NOX2/NOX4-associated oxidative stress contributes to G6PD-associated metabolic remodeling and ferroptosis during mice luteolysis.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"31 1","pages":"2724653"},"PeriodicalIF":6.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13552298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Significance of GSH and H₂S regulation for cancer: an intricate interplay between diet, microbiota, metabolic reprogramming, and immune health.","authors":"Avisek Majumder, Suravi Majumder, Shabana Bano, Koushik Sen, Kasturi Bala Nayak","doi":"10.1080/13510002.2026.2687238","DOIUrl":"10.1080/13510002.2026.2687238","url":null,"abstract":"<p><p>Due to the proliferative nature of cancer cells, they utilize more dietary extracellular nutrients via one-carbon metabolism for the various metabolic processes, including the synthesis of antioxidants such as glutathione (GSH) and hydrogen sulfide (H₂S). Indeed, several studies have found that specific cancer types produce significantly higher levels of GSH and H₂S than normal healthy cells, which may serve as a protective mechanism, allowing them to resist stress, survive, and grow. This metabolic heterogeneity, driven by intrinsic and extrinsic factors, contributes to the distinct metabolic characteristics and vulnerabilities of tumor subtypes, which can be exploited to develop anticancer strategies. In this review, we summarize the fundamental roles and regulation of GSH and H₂S in normal physiological systems and in the genesis and progression of cancer, their effects on the tumor microenvironment (TME), and their contribution to drug resistance. We also discuss the influences of diet and the gut microbiome on GSH and H₂S production, and how cancer cells reprogram their metabolism to grow and survive in a stressful environment by overproducing GSH and H₂S.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"31 1","pages":"2687238"},"PeriodicalIF":6.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13262104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148227468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating the protective role of quercetin against lipopolysaccharide-induced necroptosis in broiler thymus: insights from Nrf2/PERK signaling based on network pharmacology and experimental validation.","authors":"Yu Xia, Ruirui Xie, Xinyu Huo, Kai Chen, Shiping Li, Shiwen Xu, Shu Li","doi":"10.1080/13510002.2026.2663621","DOIUrl":"10.1080/13510002.2026.2663621","url":null,"abstract":"<p><strong>Objectives: </strong>Quercetin (QUE) possesses antioxidant, anti-inflammatory, and immunomodulatory functions. Nuclear factor erythroid 2-related factor 2 (Nrf2) can initiate protein kinase RNA-like ER kinase (PERK), leading to immune dysfunction and necroptosis. Our findings elucidate the therapeutic potential of QUE in attenuating LPS-induced injury in immune tissues.</p><p><strong>Methods: </strong>Broilers and MSB-1 cells were treated with LPS or/and QUE. We also treated MSB-1 cells with an Nrf2 inhibitor (ML385), a PERK activator (MK-28), and a necroptosis inhibitor (NSA) to further explore the detailed mechanism. In addition, we further conducted network pharmacology and bioinformatics to analyze the regulatory relationship between QUE and genes.</p><p><strong>Results: </strong>Combined analysis of network pharmacology and bioinformatics uncovered QUE regulates Nrf2 activation and its crosstalk with PERK signaling, influencing calcium homeostasis, necroptosis, and inflammation. Based on experimental validation, our findings demonstrated QUE treatment reduced LPS-induced imbalance in redox homeostasis through Nrf2 signaling pathway. QUE treatment downregulated the expression of cytokines linked to ERS, necroptosis, and inflammation. In addition, QUE treatment protected against LPS-induced immune function disorders.</p><p><strong>Conclusion: </strong>QUE treatment efficiently attenuated thymus immune disorders and necroptosis in broilers through Nrf2/PERK signaling. This investigation enriches biological function of QUE, providing a solid foundation for developing its potential application.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"31 1","pages":"2663621"},"PeriodicalIF":6.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13126941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox protection by bacterial glutathione peroxidase drives virulence in <i>Pseudomonas aeruginosa</i>.","authors":"Jadye da Silva Cordeiro, Thiago Macêdo Lopes Correia, Igor Pereira Ribeiro Muniz, Railmara Pereira da Silva, Talita Costa Dos Santos, Leonardo Silva Rocha, Regiane Yatsuda, Julia de Oliveira Borges, Albert Souza Peixoto, Amélia Cristina Mendes de Magalhães, Robson Amaro Augusto da Silva, Flávia Carla Meotti, Raphael Ferreira Queiroz","doi":"10.1080/13510002.2026.2676357","DOIUrl":"10.1080/13510002.2026.2676357","url":null,"abstract":"<p><strong>Background: </strong><i>Pseudomonas aeruginosa</i> relies on antioxidant enzymes to withstand host-derived oxidative stress during infection. Here, we investigated the role of bacterial glutathione peroxidase (GPx) in survival and virulence of the PA14 strain under inflammatory conditions associated with hyperuricemia.</p><p><strong>Methods: </strong>Wild-type (WT) and <i>Δgpx</i> strains were exposed to isolated hypochlorous acid (HOCl), hydrogen peroxide (H₂O₂), tert-butyl hydroperoxide, and urate hydroperoxide (HOOU) or challenged with human neutrophils in the presence or absence of oxidative burst modulators. <i>In vivo</i>, normouricemic and potassium oxonate-induced hyperuricemic mice were intranasally infected with WT or <i>Δgpx</i> strains to assess bacterial burden, inflammation, oxidative damage, and survival.</p><p><strong>Results: </strong>Deletion of <i>gpx</i> increased bacterial susceptibility to all oxidants, particularly HOOU, and significantly reduced survival in activated neutrophils. In mice, <i>Δgpx</i> infection resulted in reduced pulmonary bacterial burden, attenuated neutrophil infiltration, lower oxidative damage, and markedly improved survival compared to WT infection, an effect exacerbated by hyperuricemia in WT-infected animals. These findings demonstrate that GPx detoxifies organic hydroperoxides generated during inflammation, enhancing <i>P. aeruginosa</i> resistance to oxidative killing and promoting virulence.</p><p><strong>Conclusion: </strong>Collectively, our results highlight the importance of redox regulation in bacterial pathogenesis and identify GPx as a potential target for redox-based anti-virulence strategies against multidrug-resistant <i>P. aeruginosa</i>.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"31 1","pages":"2676357"},"PeriodicalIF":6.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147988500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 via HIF-1α-glycolysis drives osteoblast ferroptosis and bone loss through an IL-6-STAT3-dependent redox axis.","authors":"Yifan Gu, Kun Wang, Yicong Wang, Ziru Wang, Yiheng Li, Lei Li, Shuai Jiang, Yu Zheng, Run Feng, Min Yang","doi":"10.1080/13510002.2026.2667673","DOIUrl":"10.1080/13510002.2026.2667673","url":null,"abstract":"<p><strong>Background: </strong>Postmenopausal osteoporosis (PMOP) is characterized by exacerbated bone resorption and inadequate bone formation, with macrophage-driven inflammation playing a key role. However, how immunometabolic reprogramming of macrophages modulates osteoblast fate remains unknown.</p><p><strong>Methods: </strong>Using integrated single-cell and bulk transcriptomics, we identified a hypermetabolic macrophage subpopulation in PMOP marrow reliant on HIF-1α-glycolysis. We pharmacologically disrupted this axis with the HDAC inhibitor valproic acid (VPA) and validated its function using the HIF-1α stabilizer DMOG. The paracrine effects on osteoblasts were assessed via conditioned medium, focusing on ferroptosis and differentiation. Therapeutic efficacy was tested in ovariectomized rats.</p><p><strong>Results: </strong>VPA upregulated HIF1AN, enhancing its binding to HIF-1α and promoting its degradation. This suppressed glycolytic flux and M1 polarization, reducing IL-6 secretion. The altered secretome protected osteoblasts from ferroptosis by inhibiting the IL-6/p-STAT3/HIF-1α/TFRC axis and rebalancing GPX4/ACSL4. Osteogenic differentiation was restored. In OVX rats, VPA improved bone mass and microstructure, effects abolished by DMOG.</p><p><strong>Conclusion: </strong>We unveil a macrophage-centric immunometabolic checkpoint that is linked to osteoblast ferroptosis via IL-6/STAT3 signaling. Targeting this HIF-1α-glycolysis axis, exemplified by VPA, represents a novel therapeutic strategy for PMOP.</p>","PeriodicalId":21096,"journal":{"name":"Redox Report","volume":"31 1","pages":"2667673"},"PeriodicalIF":6.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13137742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}