Free Radical Biology and Medicine最新文献

{"title":"The non-metabolic role of MTHFD2 in regulating mitochondrial fission-dependent mitophagy via stabilizing TOP2A mRNA in glioblastoma","authors":"Zhuolin Du ,&nbsp;Xingwu Liu ,&nbsp;Yanhan Yang ,&nbsp;Xudong Min ,&nbsp;Jirui Wei ,&nbsp;Yang She ,&nbsp;Abudushalamu Abulaiti ,&nbsp;Xiayu Jin ,&nbsp;Zequn Su ,&nbsp;Shizhong Zhang ,&nbsp;Jian Liu ,&nbsp;Karrie M. Kiang ,&nbsp;Gilberto Ka-Kit Leung ,&nbsp;Xiaozheng He ,&nbsp;Zhiyuan Zhu","doi":"10.1016/j.freeradbiomed.2026.01.016","DOIUrl":"10.1016/j.freeradbiomed.2026.01.016","url":null,"abstract":"<div><div>Mitochondrial integrity is essential for tumor cell proliferation and survival. Our previous study has demonstrated the oncogenic role of the metabolic enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in glioblastoma (GBM). Given that the non-metabolic function of certain enzymes has been reported, we aim to interrogate whether MTHFD2 has potential roles in mitochondrial integrity and dynamics, especially beyond catabolism. By using multi-faceted approaches including single-cell RNA sequencing, mt-Keima mitophagy flux assays, RNA immunoprecipitation sequencing and luciferase reporter assays, we elucidated a novel, non-canonical function of MTHFD2 in stabilizing mRNA in GBM. We found that MTHFD2 was upregulated in GBM and was enriched in specific tumor subtypes cells such as ependymal-like and OPC-like cells. Knockdown of MTHFD2 profoundly promoted mitochondrial fission that triggered excessive mitophagy and cellular apoptosis. Mechanistically, MTHFD2 directly bound to the 3′-untranslated region (3′-UTR) of TOP2A mRNA and enhanced its stability, implying the RNA binding function of this catabolic enzyme. Overexpression of TOP2A attenuated mitophagy and cellular apoptosis induced by MTHFD2 depletion, indicating a vital role of MTHFD2-TOP2A axis in modulating mitochondrial integrity. Importantly, targeting MTHFD2 impeded GBM growth in orthotopic mouse models, which could be a promising therapeutic strategy. In conclusion, we proposed a non-canonical function of MTHFD2, which bound to and stabilized the mRNA of TOP2A. Targeting MTHFD2 triggered excessive mitophagy and cell apoptosis in GBM via destabilizing TOP2A mRNA.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 93-106"},"PeriodicalIF":8.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957675","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":"Redox-driven FABP1/PPARγ signaling fuels peroxisomal fatty acid oxidation and confers cetuximab resistance in drug-tolerant head and neck cancer cells","authors":"Hang Huong Ling ,&nbsp;Chin-Sheng Huang ,&nbsp;Ming-Shou Hsieh ,&nbsp;Vijesh Kumar Yadav ,&nbsp;Iat-Hang Fong ,&nbsp;Kuang-Tai Kuo ,&nbsp;Chi-Tai Yeh ,&nbsp;Jo-Ting Tsai","doi":"10.1016/j.freeradbiomed.2026.01.020","DOIUrl":"10.1016/j.freeradbiomed.2026.01.020","url":null,"abstract":"<div><div>Cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is increasingly recognized as an adaptive state driven by metabolic and redox reprogramming that enables tumor cells to tolerate sustained oxidative and immune stress. Although lipid metabolism and PPARγ signaling have been implicated in therapeutic resistance, their functional contribution to drug-tolerant persister (DTP) cells and the role of peroxisomal fatty acid oxidation (FAO) remain poorly defined. In this study, we demonstrate that a redox-driven FABP1/PPARγ axis sustains peroxisome-centered FAO, GPX4-dependent antioxidant defense, and immune suppression in cetuximab-tolerant HNSCC. FABP1 expression was markedly elevated in cetuximab-tolerant DTP cell models and resistant patient tumors. Genetic silencing or pharmacological inhibition of FABP1 using a selective small-molecule inhibitor impaired tumorsphere formation, increased intracellular reactive oxygen species accumulation, and induced apoptotic cell death, accompanied by coordinated suppression of FAO-associated genes, including CPT1, ACSL family members, and acyl-CoA oxidase 1. In an orthotopic SCC9-DTP xenograft model established in NOD-SCID mice, FABP1 inhibition significantly attenuated tumor growth, disrupted metabolic–redox adaptation, and reduced tumor-associated macrophage polarization toward an immunosuppressive phenotype. Our findings identify the FABP1/PPARγ axis as a central regulator of peroxisome-centered FAO and redox buffering in cetuximab-tolerant DTP cells. Targeting FABP1 collapses this adaptive metabolic–redox program, restores vulnerability to oxidative stress, and alleviates immune suppression, highlighting peroxisomal lipid metabolism as a therapeutically actionable vulnerability in refractory HNSCC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 209-222"},"PeriodicalIF":8.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984763","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":"Mitochondrial DNA 6 mA methylation by METTL4 drives neuroinflammation via cGAS-STING activation in vascular cognitive impairment","authors":"Zhe Gong ,&nbsp;Ziyi Chen ,&nbsp;Shuixian Sang ,&nbsp;Lingfei Yang ,&nbsp;Hongzhuo Qin ,&nbsp;Qingsheng Li ,&nbsp;Yanjie Jia","doi":"10.1016/j.freeradbiomed.2026.01.019","DOIUrl":"10.1016/j.freeradbiomed.2026.01.019","url":null,"abstract":"<div><h3>Background</h3><div>Vascular cognitive impairment (VCI) is strongly associated with mitochondrial dysfunction, yet the underlying molecular mechanisms connecting mitochondrial impairment to neuroinflammation remain elusive. While mitochondrial epigenetic modifications are emerging as key regulators of cellular metabolism, the role of mitochondrial DNA (mtDNA) N⁶-methyladenine (6 mA) modification and its writer enzyme METTL4 in VCI pathogenesis has not been established.</div></div><div><h3>Methods</h3><div>Using complementary in <em>vitro</em> (oxygen-glucose deprivation, OGD) and in <em>vivo</em> (chronic cerebral hypoperfusion, CCH) models of VCI, we systematically investigated METTL4-mediated mtDNA epigenetic regulation. Approaches included RNA sequencing (RNA-seq), mitochondrial functional assays, reactive oxygen species (ROS) measurement, and comprehensive analysis of cGAS-STING-mediated neuroinflammatory responses.</div></div><div><h3>Results</h3><div>We identified mitochondrial-specific enrichment of METTL4 in hippocampal neurons, with significantly elevated mtDNA 6 mA levels following CCH. Mechanistically, OGD-induced METTL4 preferentially methylated the light-strand promoter region of mtDNA, leading to (Dichgans and Leys, 2017) [1]: impaired electron transport chain (ETC) activity (Kim et al., 2020) [2], excessive ROS production, and (Johnson, 2023) [3] oxidized mtDNA leakage. These mitochondrial abnormalities robustly activated the cGAS-STING neuroinflammatory pathway. Genetic inhibition of METTL4 normalized 6 mA levels, restored mitochondrial gene expression profiles, and significantly improved cognitive function in VCI models.</div></div><div><h3>Conclusion</h3><div>Our study delineates a complete METTL4-mtDNA 6 mA-mitochondrial dysfunction-neuroinflammation axis in VCI pathogenesis. These findings not only provide novel insights into the epigenetic control of neuroinflammation but also position METTL4 as a promising therapeutic target for mitigating cerebrovascular-related cognitive decline.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 1-16"},"PeriodicalIF":8.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957654","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":"USP47 stabilizes HDAC2 to ameliorate cigarette smoke-induced skeletal muscle atrophy by suppressing CYP1A1/ROS-mediated autophagy","authors":"Chao Li ,&nbsp;MingZhi Ou ,&nbsp;GuiXian Zheng ,&nbsp;Gang Jiang ,&nbsp;Xiao Hu ,&nbsp;YongLiang Jiang","doi":"10.1016/j.freeradbiomed.2026.01.018","DOIUrl":"10.1016/j.freeradbiomed.2026.01.018","url":null,"abstract":"<div><div>Skeletal muscle atrophy, a debilitating complication of COPD, is closely linked to cigarette smoke (CS) exposure. The epigenetic regulator HDAC2 has been implicated, but the upstream regulatory mechanisms and precise downstream pathways are unclear. Using a CS-induced mouse atrophy model and C2C12 myotubes treated with cigarette smoke extract (CSE), we systematically investigated the role of USP47/HDAC2/CYP1A1/ROS axis through gain/loss-of-function studies, RNA-seq, ChIP-qPCR, co-immunoprecipitation, and ubiquitination assays. HDAC2 was downregulated in atrophic muscle, and its overexpression mitigated CS-induced atrophy, improved grip strength, and enhanced muscle regeneration. HDAC2 acted as a transcriptional repressor of CYP1A1 by deacetylating H3K9 and H3K27 at the promoter, thus curtailing ROS-driven excessive autophagy. We further discovered that the deubiquitinase USP47 is the key upstream regulator of HDAC2. USP47 directly interacted with HDAC2, promoted its deubiquitination, and enhanced its protein stability. Consequently, USP47 overexpression phenocopied the benefits of HDAC2 overexpression, which were effectively nullified by restoring CYP1A1 expression. In conclusion, we delineate a previously unrecognized signaling axis wherein USP47 stabilizes HDAC2 to inhibit the CYP1A1/ROS/autophagy cascade, ultimately protecting against CS-induced skeletal muscle atrophy. Targeting the USP47-HDAC2 interface presents a novel therapeutic strategy for combating muscle wasting in COPD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 107-125"},"PeriodicalIF":8.2,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965650","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":"TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover","authors":"Yixiao Xu ,&nbsp;Yishun Gong ,&nbsp;Jiafa Zhong ,&nbsp;Jiucun Wang ,&nbsp;Binghong Gao","doi":"10.1016/j.freeradbiomed.2026.01.015","DOIUrl":"10.1016/j.freeradbiomed.2026.01.015","url":null,"abstract":"<div><h3>Objective</h3><div>Active heat acclimation is widely used by athletes or workers exposed to heat, yet its impact on skeletal muscle mitochondrial function and the underlying molecular regulators remain incompletely understood. This study aimed to investigate how active heat acclimation improves skeletal muscle mitochondrial function, with a specific focus on transient receptor potential vanilloid 1 (TRPV1) as an important mediator.</div></div><div><h3>Methods</h3><div>A 4-week intervention was conducted in trained runners (exercise in heat vs. thermoneutral conditions) and in mice exposed to heat, exercise, TRPV1 activation (nonivamide), or TRPV1 inhibition (AMG9810). Aerobic performance, substrate utilization, mitochondrial respiration, H₂O₂ emission, mitochondrial ultrastructure, and molecular markers of biogenesis and mitophagy were assessed.</div></div><div><h3>Results</h3><div>In humans, active heat acclimation improved ventilatory thresholds, enhanced lactate clearance, and reduced carbohydrate oxidation during submaximal exercise. In mice, active heat acclimation increased mitochondrial biogenesis (PGC-1α, p-p38 MAPK, TFAM), enhanced mitophagy (Pink1, Parkin), improved OXPHOS and ETS capacities, and elevated TRPV1 expression. Pharmacological TRPV1 activation augmented mitochondrial remodeling and improved exercise performance. Conversely, TRPV1 inhibition blunted heat-induced mitochondrial biogenesis, mitophagy activation, and structural remodeling.</div></div><div><h3>Conclusion</h3><div>TRPV1 is an important mediator of mitochondrial adaptations to active heat acclimation, promoting mitochondrial turnover and enhancing respiratory capacity, thereby supporting the improvement of aerobic capacity.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 368-380"},"PeriodicalIF":8.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951799","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":"Dihydroartemisinin targets GPX4 to induce autophagy-dependent ferroptosis and reduce radioresistance in triple-negative breast cancer","authors":"Youyi Wu ,&nbsp;Dan Chen ,&nbsp;Xiaohu Wang ,&nbsp;Mengyao Song ,&nbsp;Jingyi Wu ,&nbsp;Shunlong Wu ,&nbsp;Kui Liao","doi":"10.1016/j.freeradbiomed.2025.12.060","DOIUrl":"10.1016/j.freeradbiomed.2025.12.060","url":null,"abstract":"<div><div>Breast cancer is one of the most common malignancies and a leading cause of mortality among women worldwide. Triple-negative breast cancer (TNBC) accounts for 15–20 % of all breast cancer cases and is characterized by poor prognosis, high invasiveness, and a propensity for metastasis. Radiotherapy is a crucial component of multimodal therapy for TNBC, serving primarily as an adjuvant modality following surgery or for local control in locally advanced disease. However, tumor tissues gradually adapt to radiation exposure, leading to the development of radioresistance—a phenomenon where cancer cells survive and proliferate despite radiotherapy, significantly compromising treatment efficacy and patient outcomes. In recent years, numerous studies have reported that the herbal compound dihydroartemisinin (DHA) may serve as a radiosensitizer to enhance tumor sensitivity to radiation while reducing radiotoxicity in surrounding normal tissues. Nevertheless, the underlying mechanisms remain insufficient to meet clinical translation demands. Thus, identifying novel targets and alternative sensitization mechanisms is urgently needed. Here, we report that DHA overcomes acquired radioresistance by orchestrating a novel autophagy-dependent ferroptosis pathway. We demonstrate that DHA directly binds to and promotes the ubiquitination-mediated degradation of GPX4, a key guardian against ferroptosis. This degradation leads to intracellular Fe²⁺ accumulation and lethal lipid peroxidation. Crucially, we establish that autophagy acts as an essential upstream mechanism enabling GPX4 degradation, thereby bridging DHA-induced stress to ferroptotic execution. Both Atg5 knockdown and pharmacological inhibition of autophagy prevented DHA-induced GPX4 loss and the consequent radiosensitization. Collectively, our findings reveal a previously unrecognized mechanism in which DHA overcomes TNBC radioresistance by co-opting the autophagy pathway to degrade GPX4 and unleash ferroptosis, presenting a promising therapeutic paradigm targeting the autophagy-ferroptosis axis for refractory TNBC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 35-50"},"PeriodicalIF":8.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951784","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-surgical periodontal treatment improves mitochondrial bioenergetics in circulating immune cells of patients with chronic periodontitis","authors":"Jonathan Hermenejildo ,&nbsp;María Pelechá-Salvador ,&nbsp;Meylin Fernández-Reyes ,&nbsp;Laura Perea-Galera ,&nbsp;Jordi Mota-Plaza ,&nbsp;Javier Silvestre-Rangil ,&nbsp;Celia Bañuls ,&nbsp;Carlos Morillas ,&nbsp;Francisco Javier Silvestre ,&nbsp;Víctor M. Víctor ,&nbsp;Sandra López-Domènech ,&nbsp;Milagros Rocha","doi":"10.1016/j.freeradbiomed.2026.01.010","DOIUrl":"10.1016/j.freeradbiomed.2026.01.010","url":null,"abstract":"<div><h3>Introduction</h3><div>Chronic periodontitis (CP) is an inflammatory disease associated with local and systemic oxidative stress and leads to mitochondrial homeostasis disruption. Although non-surgical periodontal therapy (NSPT) has been proved to reduce the bacterial load and inflammation, the mechanisms underlying its effects on mitochondrial function and systemic redox balance remain poorly understood.</div></div><div><h3>Methods</h3><div>Eighty patients with CP underwent NSPT. Clinical, anthropometric, and biochemical parameters were evaluated at baseline and 12 weeks after therapy. Mitochondrial redox status, membrane potential, markers of mitochondrial biogenic signalling (PGC-1α), electron transport chain (ETC) complexes, and bioenergetic function were assessed in peripheral blood mononuclear cells (PBMCs). Correlation and multivariable analyses were performed to explore relationships between periodontal improvement and mitochondrial parameters.</div></div><div><h3>Results</h3><div>After NSPT, patients presented significant reductions in mitochondrial ROS and increased GPX1 expression. PBMCs also showed elevated PGC-1α and ETC I–IV protein levels, together with enhanced mitochondrial membrane potential, mass, and spare respiratory capacity. Baseline mitochondrial parameters were associated with the percentage of reduction of periodontal clinical parameters following NSPT.</div></div><div><h3>Conclusions</h3><div>NSPT not only ameliorates local periodontal inflammation but also modulates mitochondrial-related homeostasis and bioenergetic efficiency in circulating immune cells. The present findings support mitochondrial remodelling as a systemic mechanism underlying the benefits of periodontal therapy and a promising target for the treatment of inflammation-related comorbidities.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 159-168"},"PeriodicalIF":8.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948772","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":"MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.","authors":"Anders Gudiksen, Camilla Collin Hansen, Thibaux van der Stede, Amalie Hertz Daugaard, Josefine H Schmidt, Stine Ringholm, Manal Merimi, Fatima Raad Al-Obaidi, Amanda Takamiya Kristoffersen, Egija Zole, Birgitte Regenberg, Rasmus Kjøbsted, Jørgen Wojtaszewski, Ylva Hellsten, Henriette Pilegaard","doi":"10.1016/j.freeradbiomed.2026.01.002","DOIUrl":"10.1016/j.freeradbiomed.2026.01.002","url":null,"abstract":"<p><p>Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTS-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"682-696"},"PeriodicalIF":8.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951795","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":"IQ-RKT Formulation mitigates cardiomyocytes injury by targeting AGEs-RAGE-ROS-dependent TRAF3IP2/JNK apoptotic nexus in diabetes","authors":"Humera Jahan ,&nbsp;Urooba Fatima ,&nbsp;Sana Asad ,&nbsp;Sidra Zahoor ,&nbsp;Priya Tufail ,&nbsp;Dania Zainab ,&nbsp;Nimra Naz Siddiqui ,&nbsp;Aaqib Ullah ,&nbsp;Marina Pizzi ,&nbsp;M. Iqbal Choudhary","doi":"10.1016/j.freeradbiomed.2026.01.004","DOIUrl":"10.1016/j.freeradbiomed.2026.01.004","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in diabetic populations. Elevated advanced glycation end products (AGEs) in diabetes foster the on-set, and progression of CVDs. However, the underlying AGEs-induced signaling nexus, involved in cardiomyocytes apoptosis, remain unexplored. Currently no anti-AGEs drug available to address CVDs in diabetes. Indeed, natural products remained a major sources of new medicine, and currently being focused in the drug development. The objective of this study was to explore the mechanism of AGEs-associated apoptotic pathway in cardiomyocytes. Additionally, to harness the medicinal properties of natural products, a newly developed formulation, comprised of <u>r</u>utin, <u>k</u>aempferol, and <u>t</u>hymoquinone, named IQ-RKT, was characterized for its anti-apoptotic potential against AGEs-induced cardiotoxicity. We studied the role of MGO-, and glucose-AGEs in cardiomyocytes apoptosis under diabetic environment in H9c2 cells <em>in vitro</em>, as well as in SD diabetic rats <em>in vivo</em>. The inhibition of AGEs-induced apoptosis of cardiomyocytes was investigated by a treatment with IQ-RKT. Using H9c2 cells, as well as SD diabetic rats models <em>in vivo</em>, we found that AGEs-induced elevated levels of RAGE was reduced by a treatment with IQ-RKT. AGEs stimulate intracellular ROS generation, TRAF3 interacting protein 2 (TRAF3IP2) expression, and TRAF3IP2-dependent-JNK activation. TRAF3IP2/JNK causes transactivation of AP-1/NF-κB transcription factors. AGEs increase Bax, cytochrome <em>c</em>, and activate caspase-3, and suppress anti-apoptotic Bcl-2. IQ-RKT significantly inhibited this apoptotic pathway, and tilted the balance towards anti-apoptosis. Moreover, IQ-RKT decreased lipid peroxidation, cardiac injury, and glycooxidative biomarkers in the plasma of diabetic rats. Interestingly, this effect of IQ-RKT was independent of hyperglycemic environment in diabetic rats. The IQ-RKT also appeared as a stable formulation at different pH, and temperature ranges. The study provides experimental evidences that AGE-RAGE axis is likely associated with cardiomyocytes death <em>via</em> ROS-dependent TRAF3IP2/JNK pathway. Therefore, targeting this pathway appeared to have therapeutic potential. The newly developed formulation IQ-RKT was identified as an effective anti-apoptotic cardioprotective agent to be further investigated through pre-clinical, and clinical studies.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 456-475"},"PeriodicalIF":8.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951793","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":"OX-LDL causes vascular endothelial injury by interfering with the CREB1-MDH1B-malate axis","authors":"Chen Pu ,&nbsp;Hailang Yang ,&nbsp;Guorong Wang ,&nbsp;Xueting Wang ,&nbsp;Xiaobin Wan ,&nbsp;Qiang Liu ,&nbsp;Yanping Zhao","doi":"10.1016/j.freeradbiomed.2025.12.051","DOIUrl":"10.1016/j.freeradbiomed.2025.12.051","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis (AS) is one of the most prevalent cardiovascular disorders, with endothelial dysfunction recognized as a central initiating event in its pathogenesis. Oxidized low-density lipoprotein (ox-LDL) is a key pathogenic factor that contributes to vascular injury. While the pro-atherogenic and oxidative effects of ox-LDL have been well described, the mechanisms by which it influences cellular energy metabolism remain largely unclear.</div></div><div><h3>Objective</h3><div>This study aims to elucidate how ox-LDL impairs endothelial cell function through repression of the transcription factor CREB1 and its downstream target gene MDH1B, leading to disrupted malate metabolism and mitochondrial dysfunction. These findings are intended to provide mechanistic insights and identify potential targets for therapeutic intervention in vascular injury.</div></div><div><h3>Methods</h3><div>Differentially expressed genes were identified by analyzing the GSE13139 dataset, and candidate genes were validated in human aortic endothelial cells (HAECs). The transcriptional regulation of MDH1B by CREB1 was investigated using RT–qPCR, Western blotting, dual-luciferase reporter assays, and ChIP–qPCR. Malate, ATP, and ADP levels were measured alongside mitochondrial membrane potential (JC-1 staining) and ultrastructural analyses by transmission electron microscopy. Functional relevance was validated in high-cholesterol diet mouse models.</div></div><div><h3>Results</h3><div>Ox-LDL suppressed CREB1 expression, phosphorylation, and nuclear translocation, resulting in downregulation of MDH1B. This repression impaired malate production, reduced mitochondrial membrane potential, and decreased ATP levels in endothelial cells. MDH1B overexpression restored malate levels, improved mitochondrial function, and attenuated ox-LDL–induced endothelial injury. Exogenous malate supplementation partially rescued metabolic deficits and cellular viability but did not restore the CREB1–MDH1B axis.</div></div><div><h3>Conclusion</h3><div>This study reveals that ox-LDL impairs endothelial function by inhibiting CREB1 phosphorylation/nuclear translocation, which suppresses MDH1B transcription. This disrupts malate metabolism, causing mitochondrial dysfunction and endothelial injury. The CREB1–MDH1B–malate axis bridges transcriptional regulation with metabolic homeostasis, offering a potential therapeutic target for ox-LDL-induced vascular injury.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"245 ","pages":"Pages 405-417"},"PeriodicalIF":8.2,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922796","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}