Antioxidants & redox signaling最新文献

{"title":"Dose-Dependent Ferroptosis Induction in Osteosarcoma via NRF2/GPX4 Axis Modulation by Plasma-Activated Liquid Therapy.","authors":"Longze Xiao, Mian Zhang, Peng He, Hao Wang, Sheng Li, Yonghong Wu, Shenglin Xu, Yong Hu","doi":"10.1177/15230864251399168","DOIUrl":"10.1177/15230864251399168","url":null,"abstract":"<p><strong>Aims: </strong>Plasma-activated liquid (PAL), an indirect application form of cold-atmospheric plasma (CAP)-an ionized gas generating reactive oxygen and nitrogen species, has been proposed as an innovative therapeutic approach for various cancer types. Despite accumulating evidence suggesting that PAL induces cell death through multiple mechanisms, the involvement of ferroptosis, a form of cell death driven by iron and lipid peroxidation, in osteosarcoma (OS) remains predominantly unknown.</p><p><strong>Results: </strong>CAP was used to activate the liquid for various durations, resulting in different doses of PAL. The antitumor efficacy of PAL was directly correlated with both the dosage and duration of treatment and was achieved by increasing the level of intracellular reactive oxygen species. Through screening three effective PAL doses, we discovered that PAL significantly influenced the migration and invasion capabilities of OS cells. Proteomic sequencing revealed increases in several ferroptosis-related antioxidant proteins in the PAL-treated group. Subsequent findings revealed that PAL modulated nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream ferroptosis-related genes, predominantly resulting in the induction of ferroptosis by depleting glutathione peroxidase 4 (GPX4) in human OS cells. Finally, utilizing an OS xenograft model, we found that PAL effectively suppressed tumor growth <i>in vivo via</i> ferroptosis.</p><p><strong>Innovation: </strong>Our study highlights the importance of the NRF2/GPX4 axis as a pivotal pathway in PAL-induced ferroptosis. <i>In vivo</i> experiments provided compelling evidence supporting the potential of PAL as a potent therapeutic strategy for OS treatment.</p><p><strong>Conclusion: </strong>High-dose PAL-induced sustained oxidative stress by simultaneously targeting NRF2 inactivation and GPX4 degradation, establishing redox imbalance as a critical ferroptotic checkpoint in OS therapy. <i>Antioxid. Redox Signal.</i> 44, 292-310.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"292-310"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145628097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polypeptide Nanomicrospheres Delivering Dexmedetomidine Mitigate Intestinal Ischemia/Reperfusion Injury by Regulating Autophagy and Inflammation.","authors":"Zhen Liu, Qian Hu, Qiuhong Chen, Qiong Wu, Sisi Liang, Jinping Nie, Chenlu Fan, Qin Zhang, Xuekang Zhang","doi":"10.1177/15230864251394744","DOIUrl":"10.1177/15230864251394744","url":null,"abstract":"<p><strong>Aims: </strong>This study aims to evaluate the protective effects of dexmedetomidine-loaded polypeptide nanomicrospheres (PNM@Dex) in a mouse model of intestinal ischemia/reperfusion (I/R) injury and investigate the underlying molecular mechanisms, focusing on autophagy activation in enteric neurons.</p><p><strong>Results: </strong>PNM@Dex, synthesized <i>via</i> solid-phase peptide synthesis and coprecipitation, exhibited uniform spherical morphology (∼150 nm) and high drug encapsulation efficiency. <i>In vitro</i> studies demonstrated that PNM@Dex promoted autophagy in enteric neurons, attenuated oxidative stress and apoptosis, and improved cell viability. <i>In vivo</i> administration significantly mitigated intestinal injury, suppressed inflammatory cytokine production, and increased the expression of autophagy-related proteins. Autophagy inhibition assays confirmed the essential role of autophagy in mediating the protective effects of PNM@Dex.</p><p><strong>Innovation: </strong>This study represents the first successful incorporation of dexmedetomidine into polypeptide nanomicrospheres for targeted delivery to enteric neurons. The nanoplatform achieved sustained release, enhanced autophagy, and exerted strong anti-inflammatory and antioxidant effects, offering a novel therapeutic approach for intestinal I/R injury and potential protection in intestinal transplantation.</p><p><strong>Conclusion: </strong>PNM@Dex effectively alleviated intestinal I/R-induced damage through autophagy induction, oxidative stress reduction, and inflammation modulation, underscoring its promise as a therapeutic strategy for intestinal protection and transplantation. <i>Antioxid. Redox Signal.</i> 44, 213-235.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"213-235"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PGK1 Persulfidation Promotes the Proliferation and Metastasis of Breast Cancer.","authors":"Chenghua Luo, Mengmeng Zhao, Yalu Wang, Yuxiang Xu, Shuai Chen, Weihua Liang, Kaige Yang, Jianming Hu","doi":"10.1177/15230864251394334","DOIUrl":"10.1177/15230864251394334","url":null,"abstract":"<p><strong>Aims: </strong>Endogenous hydrogen sulfide (H₂S) is involved in the occurrence and development of breast cancer, while its underlying mechanism is not yet clear. Here, we aimed to focus on the molecular mechanism of endogenous H₂S promoting the proliferation and metastasis of breast cancer.</p><p><strong>Results: </strong>In this study, four major findings were revealed: (1) Inhibition of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) increased the content of glucose in the supernatant of breast cancer cell and decreased the production of intracellular lactic acid and adenosine triphosphate. (2) Phosphoglycerate kinase 1 (PGK1) was persulfidated at Cys108 and Cys316, and its persulfidation level in breast cancer tissue was significantly higher than that in paracancerous tissue. (3) Blocking the persulfidation of PGK1 inhibited glycolysis and malignant biological behaviors of breast cancer cell. (4) The CSE inhibitor reduced the persulfidation of PGK1 and inhibited the growth and metastasis of xenograft tumors, whereas sodium hydrosulfide reversed the effect of CSE inhibitor. Preface PGK1 is not the only potential target for persulfidation.</p><p><strong>Innovation and conclusion: </strong>This study revealed a novel mechanism involved in the upregulation of endogenous H₂S in breast cancer. Endogenous H₂S regulates glycolysis of breast cancer cells by mediating PGK1 persulfidation modification at Cys108 and Cys316, thereby promoting tumor proliferation and metastasis. This study offers a potential therapeutic strategy through targeting the upregulated endogenous H₂S and persulfidation of PGK1. <i>Antioxid. Redox Signal.</i> 44, 164-181.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"164-181"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis in Tubular Epithelial Cells Across Distinct Renal Regions Is a Primary Causal Factor for Lupus Nephritis.","authors":"Wumeng Jin, Hualing Chen, Shuanglin Zhang, Xiaofen Xu, Peng Zhao, Xuanming Hu, Guanqun Xie, Yu Du, Chengping Wen, Lu Lu, Changfeng Hu","doi":"10.1177/15230864251396446","DOIUrl":"10.1177/15230864251396446","url":null,"abstract":"<p><strong>Aims: </strong>Ferroptosis has been implicated in the pathogenesis of lupus nephritis (LN), yet its precise role and mechanisms remain unclear. This study aimed to clarify the role of ferroptosis in LN progression and its underlying mechanisms.</p><p><strong>Methods: </strong>Transmission electron microscopy (TEM) was used to assess mitochondrial morphology in renal tissues from LN patients and MRL/<i>lpr</i> mice. Multidimensional mass spectrometry-based shotgun lipidomics was applied to analyze lipid alterations in renal cortex, medulla, and isolated renal tubules. Immunoblotting and reverse transcription quantitative PCR were performed to evaluate ferroptosis-related proteins and their messenger RNAs (mRNAs). Primary renal tubular epithelial cells (RTECs) from the distinct renal regions (cortex/medulla) were isolated and exposed to oxidative stress <i>in vitro</i>. Ferroptosis inducer erastin and inhibitor ferrostatin-1 (Fer-1) were used <i>in vivo</i> to determine causal effects.</p><p><strong>Results: </strong>TEM revealed typical ferroptotic mitochondrial changes in renal tissues from both LN patients and lupus-prone mice. In MRL/<i>lpr</i> mice, ferroptosis occurred as early as the pre-LN stage (8 weeks) and worsened by 14 weeks, with cortical tubules showing more severe damage than medullary tubules. Lipidomics demonstrated significant increases in lysophospholipids (<i>e.g.,</i> 22:4 lysophosphatidylethanolamine, <i>p</i> < 0.001; 20:4 lysophosphatidylcholine, <i>p</i> < 0.01) and HNE species (<i>p</i> < 0.05), along with reductions in plasmalogens (<i>e.g.,</i> 18:1-20:4 plasmenylcholine, <i>p</i> < 0.001). Mechanistically, ferroptosis was driven by downregulation of glutathione peroxidase 4 (<i>p</i> < 0.001) and solute carrier family 7 member 11 (<i>p</i> < 0.01) and upregulation of Acyl-CoA synthetase long chain family member 4 (<i>p</i> < 0.05), consistent with mRNA changes. Functionally, cortical RTECs cultured <i>in vitro</i> exhibited higher lipid reactive oxygen species (<i>p</i> < 0.001) and ferrous ion (Fe²⁺) accumulation (<i>p</i> < 0.01). <i>In vivo</i>, erastin accelerated LN progression, whereas Fer-1 significantly reduced proteinuria, renal pathology, and inflammatory cytokines.</p><p><strong>Innovation and conclusion: </strong>The study provided direct evidence of ferroptosis markers in renal tissues of LN patients. RTECs exhibited the intrinsic abnormalities that trigger ferroptosis, greatly contributing to the progression of LN. Our findings highlighted the critical role of region-specific tubular ferroptosis in driving renal pathology. Early intervention targeting ferroptosis of RTECs in the renal cortex might be an effective strategy for treating LN. <i>Antioxid. Redox Signal.</i> 44, 197-212.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"197-212"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytokine-Microglia Interactions in Neuroinflammation: Mechanisms, Disease Dynamics, and Therapeutic Strategies.","authors":"Fumei Zhang, Wenren Yang, Rong Sun, Xiaoyu Duan, Yunhua Yang, Aiping Wang, Ying Tian","doi":"10.1177/15230864251401591","DOIUrl":"10.1177/15230864251401591","url":null,"abstract":"<p><p>Neuroinflammation contributes to the onset and progression of a variety of central nervous system (CNS) diseases, including ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, intracerebral hemorrhage, and neurodevelopmental disorders related diseases. Microglia are essential for the neurodevelopment of a healthy brain and the integrity of the blood-brain barrier. Activation of microglia is the brain's defense mechanism against damaged tissues and harmful pathogens. However, their activation can trigger neuroinflammation, which can exacerbate or induce damage to the CNS. Cytokines are small proteins that can act in either an autocrine or paracrine manner. Cytokines are highly expressed in microglia and are potential mediators of neuroinflammation. We review the recent research progress on the role of cytokines such as interleukin-1 (IL-1β), tumor necrosis factor-α , IL-6, IL-4, and transforming growth factor-β in regulating neuroinflammation in various CNS diseases. Understanding how these cytokines affect microglia-mediated neuroinflammation will provide important therapeutic insights for preventing and managing CNS dysfunction, with potential clinical relevance for developing targeted anti-inflammatory therapies and biomarker-based diagnostic strategies. <i>Antioxid. Redox Signal.</i> 44, 311-331.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"311-331"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145832911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Nutritional Epidemiology to Clinical Translation: Machine Learning Uncovers Antioxidant-Driven Prevention Strategies for Mitigating Cardiovascular-Arthritis Multimorbidity.","authors":"Jingkai Di, Liying Song, Yinqi Long, Yicong Zhao, Zijian Guo, Yingda Qin, Chuan Xiang","doi":"10.1177/15230864251401537","DOIUrl":"10.1177/15230864251401537","url":null,"abstract":"<p><strong>Background: </strong>The aim of this study was to construct a machine learning (ML) model to predict the effect of dietary antioxidants on cardiovascular-arthritis comorbidity.</p><p><strong>Methods: </strong>In this study, 44 dietary antioxidants were selected based on the National Health and Nutrition Examination Survey data from 2007 to 2010 and from 2017 to 2018, and demographic covariates such as gender and age were included for analysis. In addition, 10 mainstream ML models were investigated for the evaluation, and a comprehensive evaluation system of the multi-indicator empowerment algorithms was constructed to comprehensively measure the model performance. To further enhance the model interpretability, SHapley Additive exPlanations (SHAP) values and Local Interpretable Model-agnostic Explanation (LIME) methods were introduced to deeply analyze the prediction mechanism.</p><p><strong>Results: </strong>A total of 8046 participants were included in this study, of whom 380 had cardiovascular disease and arthritis comorbidities. After multiple covariates were eliminated, 34 indicators of nutritional antioxidant intake and 11 demographic baseline characteristics were selected as key predictors. The multicriteria-based assessment system demonstrated excellent performance of the logistic regression machine model. It performed optimally on the validation set with an area under the receiver operating characteristic curve of 0.871. Notably, the study of SHAP and LIME algorithms revealed the opposite biological effects of total and single flavonoid intake as well as the heterogeneity of dietary antioxidants in different age-sex characterized populations.</p><p><strong>Conclusion: </strong>This study suggests that future strategies should consider antioxidant types and individual traits, promoting diverse natural foods over single supplements to advance precision nutrition. <i>Antioxid. Redox Signal.</i> 44, 251-270.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"251-270"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-thermal Plasma-Derived Reactive Oxygen Species Induces Cell Death in Radioresistant Head and Neck Cancer <i>via</i> the c-MET/STAT3 Pathway.","authors":"Chan Oh, Mi Ae Lim, Shengzhe Cui, Yudan Piao, Sicong Zheng, Yan Li Jin, Shan Shen, Quoc Khanh Nguyen, Se-Hee Park, Young Il Kim, Jae Won Chang, Ho-Ryun Won, Ji Won Kim, Seung-Nam Jung, Bon Seok Koo","doi":"10.1177/15230864251393938","DOIUrl":"10.1177/15230864251393938","url":null,"abstract":"<p><strong>Aims: </strong>Radiation therapy is a crucial treatment modality for head and neck squamous cell carcinomas (HNSCCs). However, acquired radiation resistance due to various mechanisms poses a major clinical challenge for therapeutic strategies. Intriguingly, reactive oxygen species (ROS) are versatile signaling molecules that promote various cellular functions at low concentrations but induce cell death at above-critical threshold levels.</p><p><strong>Results: </strong>Here, we found that radioresistant (RR) cancer cells exhibited reduced ROS levels and activation of the mesenchymal-epithelial transition factor/signal transducer and activator of transcription 3 (c-MET/STAT3) pathway. To target common vulnerabilities in RR cancers, we applied ROS enhancement therapy using nonthermal plasma-activated media (NTPAM), a novel approach that effectively inhibits the viability of RR cancer cells and is associated with inactivation of the c-MET/STAT3 pathway. Mechanistically, the downregulation of total c-MET is related to ROS-mediated lysosomal degradation. In addition, NTPAM suppressed tumor growth in a mouse model of RR cancer, concurrently reducing the levels of both the total and activated forms of c-MET and decreasing STAT3 phosphorylation.Innovations and Conclusions:These findings suggest that ROS enhancement therapy can overcome radiation resistance, thereby offering a compelling rationale for considering NTPAM as a stand-alone or complementary therapeutic approach for treating patients with HNSCCs. <i>Antioxid. Redox Signal.</i> 44, 182-196.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"182-196"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinoic Acid Receptor-related Orphan Receptor α Drives Glucose Reprogramming and Mitochondrial Rescue Mitigate Subarachnoid Hemorrhage-Induced Early Brain Injury.","authors":"Jie Li, Jiaqi Wang, Sijing Guo, Fengchen Zhang, Yichao Jin, Xiaohua Zhang","doi":"10.1177/15230864251399609","DOIUrl":"10.1177/15230864251399609","url":null,"abstract":"<p><strong>Aims: </strong>Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular event characterized by early brain injury (EBI) within 72 h that is driven by oxidative stress, mitochondrial dysfunction, and metabolic collapse. The retinoic acid receptor-related orphan receptor alpha (RORα) is a nuclear receptor implicated in metabolic and inflammatory regulation, but it has not been studied in SAH. We aimed to determine whether RORα confers neuroprotection after SAH and to elucidate its underlying mechanisms.</p><p><strong>Methods and results: </strong>We used mouse SAH models and primary cortical neurons to assess the RORα expression, functional outcomes, and metabolic changes. The RORα expression was markedly reduced post-SAH. Genetic knockdown or deficiency (staggerer mice) exacerbated neuronal apoptosis, neuroinflammation, and behavioral deficits. Conversely, pharmacological activation with SR1078 significantly improved neurological scores, preserved neuronal morphology, and reduced oxidative stress. RORα overexpression or SR1078 treatment enhanced neuronal viability <i>in vitro</i> under hemoglobin-induced stress. Transcriptomic and epigenomic profiling revealed that RORα directly regulated glucose-6-phosphate dehydrogenase and α subunit of peroxisome proliferator activated receptor-γ coactivator-1. This promoted pentose phosphate pathway flux and mitochondrial biogenesis. A metabolic flux analysis confirmed increased nicotinamide adenine dinucleotide phosphate hydrogen and glutathione synthesis, reduced reactive oxygen species accumulation, and an improved oxygen consumption rate and spare respiratory capacity. All of these results indicated a shift toward oxidative phosphorylation and enhanced bioenergetics.</p><p><strong>Innovation and conclusion: </strong>We are the first to demonstrate that RORα activation reprogrammed neuronal glucose metabolism and strengthened antioxidant defenses to mitigate SAH-induced EBI. The targeting of RORα could represent a promising therapeutic strategy for stroke-related metabolic failure and oxidative stress. Future work should explore the translational potential in clinical settings. <i>Antioxid. Redox Signal.</i> 44, 275-291.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"275-291"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atraric Acid Mitigates Mitochondrial Dysfunction and Inflammation via AMPKα-PGC-1α Signaling in Metabolic-Associated Fatty Liver Disease.","authors":"Yannan Xiang, Zhihao Ma, Tianyue Guan, Hongyu Huang, Xinran Li, Zihan Xu, Panpan Zhao, Lei Wang","doi":"10.1177/15230864251406293","DOIUrl":"10.1177/15230864251406293","url":null,"abstract":"<p><strong>Background: </strong>Metabolic-associated fatty liver disease (MASLD) is a leading cause of chronic liver injury worldwide, characterized by hepatic lipid accumulation, oxidative stress, inflammation, and mitochondrial dysfunction. Despite its prevalence, no approved pharmacological treatments currently exist. Atraric acid (AA), a natural compound with antioxidant and anti-inflammatory properties, has not been previously investigated in MASLD.</p><p><strong>Objective: </strong>This study aimed to evaluate the therapeutic potential of AA and elucidate its underlying mechanisms in MASLD.</p><p><strong>Methods: </strong>MASLD was modeled in mice using a high-fat diet and in alpha mouse liver 12 hepatocytes using oleic acid/palmitic acid. AA's effects on liver injury, mitochondrial function, and inflammatory signaling were assessed through biochemical assays, histology, transcriptomic analysis, and mechanistic studies involving adenosine 5'-monophosphate-activated protein kinase (AMPK) inhibition and liver-specific AMPK knockout models.</p><p><strong>Results: </strong>AA significantly improved hepatic steatosis, reduced serum alanine transaminase and aspartate aminotransferase levels, and alleviated inflammation in MASLD mice. <i>In vitro</i>, AA restored mitochondrial membrane potential, enhanced adenosine triphosphate production, and suppressed reactive oxygen species accumulation and NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome activation. Mechanistically, AA directly interacted with AMPK, promoted its phosphorylation, and upregulated peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α), thereby improving mitochondrial biogenesis and redox balance. These protective effects were abolished by AMPKα inhibition or knockout, confirming AMPK as a key mediator. Additionally, AA modulated related pathways, including SIRT1 and mTOR, suggesting broader metabolic benefits.</p><p><strong>Conclusion: </strong>AA mitigates MASLD by activating the AMPK-PGC-1α axis, restoring mitochondrial function, and reducing ROS-driven inflammation. These findings highlight AA as a promising candidate for MASLD therapy and warrant further clinical investigation. <i>Antioxid. Redox Signal.</i> 44, 332-356.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"332-356"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145853267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 6 Protects Cartilage from Diabetes-Driven Degeneration by Blocking Ferroptosis: A New Therapeutic Target for Osteoarthritis.","authors":"Yang Chen, Yao Li, Deping Chen, Jiajie Yang, Hui Kang, Fangxing Wang","doi":"10.1177/15230864251410881","DOIUrl":"10.1177/15230864251410881","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA), characterized by articular cartilage degeneration, is exacerbated by diabetes mellitus (DM), an independent risk factor whose molecular mechanisms remain incompletely understood. This study investigates novel regulators and pathways underlying DM-associated OA pathogenesis.</p><p><strong>Methods: </strong>We used bioinformatic analysis of transcriptomic data from OA and diabetic OA (DM-OA) cohorts to identify differentially expressed genes. We constructed functional enrichment and protein-protein interaction (PPI) networks. <i>In vivo</i>, we modeled diabetic OA in mice <i>via</i> high-fat diet/streptozotocin induction combined with destabilization of the medial meniscus surgery. <i>In vitro</i>, we exposed chondrocytes to high glucose to mimic diabetic conditions. We genetically modulated leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) through chondrocyte-specific knockout (KO) in LGR6-deficient mice and overexpression (OE) <i>via</i> intra-articular delivery of adeno-associated virus serotype 9. We validated key molecular changes using quantitative reverse transcription polymerase chain reaction, Western blotting, immunohistochemistry, and ferroptosis-associated assays (reactive oxygen species, glutathione, malondialdehyde [MDA], and mitochondrial morphology).</p><p><strong>Results: </strong>LGR6 expression was significantly downregulated in DM-OA cartilage. PPI analysis highlighted interactions between LGR6, collagen type II (COL2A1), and matrix metalloproteinase (MMP)13. LGR6 KO exacerbated OA severity, cartilage degradation, and inflammatory markers (MMP3, MMP13, and nitric oxide synthase-2) while reducing extracellular matrix (ECM) components (COL2A1 and SRY-box transcription factor 9). Conversely, LGR6 OE attenuated cartilage damage, suppressed catabolic factors, and restored ECM synthesis. Mechanistically, LGR6 deficiency intensified ferroptosis, evidenced by elevated lipid peroxidation (MDA), mitochondrial cristae disruption, and dysregulation of glutathione peroxidase 4/prostaglandin-endoperoxide synthase 2. LGR6 activation reversed these effects, restoring redox homeostasis and mitochondrial integrity.</p><p><strong>Innovation: </strong>This study identifies LGR6 as a pivotal inhibitor of chondrocyte ferroptosis in DM-OA, revealing a previously unexplored link between hyperglycemia, mitochondrial dysfunction, and iron-dependent cell death.</p><p><strong>Conclusion: </strong>LGR6 safeguards cartilage by suppressing ferroptosis and maintaining mitochondrial biogenesis in diabetic conditions. Targeting the LGR6 pathway offers a promising therapeutic strategy for DM-associated OA. <i>Antioxid. Redox Signal.</i> 44, 357-372.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"357-372"},"PeriodicalIF":6.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146058974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}