Free Radical Biology and Medicine最新文献

{"title":"Insulin-like growth factor 2 mRNA-binding Protein 2 regulates PINK1 expression through m6A pathway to promote mitophagy in BMSCs alleviating postmenopausal osteoporosis","authors":"Yu Ji ,&nbsp;Yajun Cui ,&nbsp;Lingshuang Li ,&nbsp;Tianyu Cao ,&nbsp;Hongrui Liu ,&nbsp;Minqi Li","doi":"10.1016/j.freeradbiomed.2026.01.038","DOIUrl":"10.1016/j.freeradbiomed.2026.01.038","url":null,"abstract":"<div><div>The senescence and altered differentiation potential of bone marrow mesenchymal stem cells (BMSCs) contribute to the pathogenesis of postmenopausal osteoporosis (PMOP). Insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) has been demonstrated to regulate BMSCs. However, its specific mechanistic actions remain unclear, particularly due to the lack of concrete evidence within the ovariectomy (OVX) <em>in vivo</em> microenvironment. In this study, we utilized Cre-LoxP technology to achieve BMSC-specific IMP2 knockout. This approach conclusively demonstrated <em>in vivo</em> that IMP2 deficiency induces BMSC senescence, suppresses osteogenic differentiation capacity, and leads to significant bone mass reduction in mice. Under OVX condition, IMP2 knockout also aggravates bone loss. Mechanistically, we argued that IMP2 stabilizes PINK1 mRNA via the N6-methyladenosine (m⁶A) pathway; upon IMP2 silencing, reduced PINK1 protein expression attenuates mitophagy in BMSCs, ultimately culminating in accelerated cellular senescence and diminished osteogenic potential, with the postmenopausal environment further aggravating this cascade.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 400-414"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046486","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 ,&nbsp;Camilla Collin Hansen ,&nbsp;Thibaux van der Stede ,&nbsp;Amalie Hertz Daugaard ,&nbsp;Josefine H. Schmidt ,&nbsp;Stine Ringholm ,&nbsp;Manal Merimi ,&nbsp;Fatima Raad Al-Obaidi ,&nbsp;Amanda Takamiya Kristoffersen ,&nbsp;Egija Zole ,&nbsp;Birgitte Regenberg ,&nbsp;Rasmus Kjøbsted ,&nbsp;Jørgen Wojtaszewski ,&nbsp;Ylva Hellsten ,&nbsp;Henriette Pilegaard","doi":"10.1016/j.freeradbiomed.2026.01.002","DOIUrl":"10.1016/j.freeradbiomed.2026.01.002","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 682-696"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","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":"Glycine ameliorates aging-related dysfunctions associated with Nmdmc-mediated mitochondrial one-carbon metabolism","authors":"Jiaying Yu ,&nbsp;Yiran Wang ,&nbsp;Nan Wang ,&nbsp;Yizhi Zhang ,&nbsp;Qi Yu ,&nbsp;Jingjing Li ,&nbsp;Runan Zhang ,&nbsp;Fanyun Wang ,&nbsp;Qianru Zhang ,&nbsp;Jiaqi Zhang ,&nbsp;Jiayu Zhu ,&nbsp;Weili Xu ,&nbsp;Bo Peng ,&nbsp;Bo Qu ,&nbsp;Liyan Liu ,&nbsp;Rennan Feng","doi":"10.1016/j.freeradbiomed.2026.01.050","DOIUrl":"10.1016/j.freeradbiomed.2026.01.050","url":null,"abstract":"<div><h3>Introduction</h3><div>Aging is characterized by the progressive decline of physiological integrity, and its driving factors include mitochondrial dysfunction, epigenetic changes and metabolic imbalance. Although some studies have shown that glycine (Gly) has anti-aging protection, its mechanism has not been clarified.</div></div><div><h3>Objectives</h3><div>The purpose of this study is to explore the mechanism of Gly in anti-aging and improving aging-related phenotype, and to clarify the molecular pathway of Gly promoting healthy aging.</div></div><div><h3>Methods</h3><div>Fruit fly and aged rat models were used to evaluate the effect of Gly supplementation. Life span, stress resistance and functional phenotype were evaluated in fruit flies, and biochemical, histological and physiological indexes related to aging were detected in aged rats. Transcriptomic and metabolomic profiling, along with gene knockdown approaches, were used to identify key pathways and targets involved in Gly-mediated effects.</div></div><div><h3>Results</h3><div>In fruit flies, Gly extended lifespan and ameliorating aging-related phenotypes, with Gly dose-dependently upregulated the expression of <em>Nmdmc</em>, whose knockdown abolished these beneficial effects, indicating the essential role of <em>Nmdmc</em> in Gly-mediated activation of one-carbon metabolism (OCM). Metabolomic identified glyceric acid as a key metabolite linked to improved mitochondrial energy metabolism. In aged rats, Gly also upregulated <em>Mthfd2</em> (the mammalian ortholog of <em>Nmdmc</em>) and reduced neuronal damage in the hippocampus, restored hepatic cell architecture, and increased muscle fiber density, accompanied by enhanced mitochondrial biogenesis and methylation markers.</div></div><div><h3>Conclusion</h3><div>Gly supplementation alleviated aging-related dysfunction by up-regulating <em>Nmdmc</em> and remodeling mitochondrial OCM, which could help to improve DNA repair, mitochondrial function and oxidative stress resistance.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 697-710"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085160","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":"Oxysterol-induced oxidative disruption of skin junction integrity","authors":"Alessandra Pecorelli ,&nbsp;Anna Guiotto ,&nbsp;Alice Casoni ,&nbsp;Marta Ruzza ,&nbsp;Lorena Beltrami ,&nbsp;Barbara Canepa ,&nbsp;Fiorella Biasi ,&nbsp;Giuseppe Poli ,&nbsp;Giuseppe Valacchi","doi":"10.1016/j.freeradbiomed.2026.01.047","DOIUrl":"10.1016/j.freeradbiomed.2026.01.047","url":null,"abstract":"<div><div>The cutaneous tissue is persistently exposed to environmental stressors, including a wide range of airborne pollutants. This chronic exposure often leads to a condition of oxidative stress, with the outermost layer of epidermis, the stratum corneum (SC), being especially vulnerable due to its high lipid content. Notably, approximately 40 % of SC lipids consist of cholesterol, present in both esterified and unesterified forms. The oxidative imbalance induced by environmental stressors and constantly associated with inflammatory skin diseases promotes the formation and accumulation of cholesterol oxidation products, belonging to the oxysterols’ family, which are known for their potent pro-oxidant and pro-inflammatory properties. In addition, harmful oxysterols of dietary origin could reach the epidermis via the vascularized dermis, thus adding another route of exposure. 7β-Hydroxycholesterol (7βOHC) and 7-ketocholesterol (7 KC), two highly toxic oxysterols of non-enzymatic origin, have been shown to significantly downregulate proteins involved in adherens and tight junctions in the intestinal epithelium. Given the structural similarity of extracellular junction proteins across tissues, it is reasonable to expect that oxysterols may similarly disrupt the integrity of the epidermal barrier. To investigate this, supraphysiologic concentrations of 7 KC and 7βOHC were added to the medium of human keratinocytes. Immunofluorescence analysis revealed a consistent and significant reduction in the levels of Claudin-1, Zonulin-1 (ZO1), and E-cadherin, key proteins of tight and adherens junctions, respectively, in oxysterol-treated cells compared to controls. Notably, oxysterol exposure also led to a reduction of mitochondrial membrane potential and an increased mitochondrial reactive oxygen species (ROS) production. Both mitochondrial damage and the disruption of skin junctions were efficiently prevented by mitoTEMPO, a selective mitochondrial superoxide scavenger, suggesting the pro-oxidant activity of oxysterols mediates these effects in keratinocytes. Finally, experiments conducted using a 3D skin model corroborated findings observed in keratinocyte cultures, reinforcing the role of oxysterols in compromising the skin barrier integrity.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 505-517"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097116","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":"Corrigendum to “An intrabody targeting PHD2 protects mice against acetaminophen-induced liver injury by attenuating ferroptosis” [Free Radic. Biol. Med. 243 (2026) 260-275]","authors":"Ze Ren,&nbsp;Ying Wang,&nbsp;Cheng Cheng,&nbsp;Yingming Zhang,&nbsp;Yanfei Liu,&nbsp;Yuchong Wei,&nbsp;Zhaoyang Liu,&nbsp;Jingyue Zhang,&nbsp;Zijian Shi,&nbsp;Jiayin Yu,&nbsp;Wanning Hu,&nbsp;Junbo Ye,&nbsp;Jianxia Wang,&nbsp;Siyu Qiu,&nbsp;Guiying Li","doi":"10.1016/j.freeradbiomed.2026.02.021","DOIUrl":"10.1016/j.freeradbiomed.2026.02.021","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 797-798"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146217886","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":"2026-03-16","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":"Protective role of cichoriin and inulin against HFD-STZ-induced diabetic cardiomyopathy in mice via oxidative stress suppression and metabolic modulation","authors":"Nayan Kumar Sishu ,&nbsp;Sajan George ,&nbsp;Chinnadurai Immanuel Selvaraj","doi":"10.1016/j.freeradbiomed.2026.02.003","DOIUrl":"10.1016/j.freeradbiomed.2026.02.003","url":null,"abstract":"<div><div>The distinctive characteristics of diabetic cardiomyopathy (DCM), a serious outcome of diabetes mellitus, are anomalies in the structure and functionality of the cardiac tissue. With a focus on their impact on inflammatory responses, oxidative injury, and the functioning of metabolic enzymes, this investigation aimed to evaluate the cardioprotective benefits of inulin and cichoriin over diabetes-related cardiomyopathy induced by high fat diet-streptozotocin (HFD-STZ) in mice. Diabetes was introduced in male Swiss albino mice by feeding them a high-fat diet followed by STZ injection and treated with cichoriin (50 and 100 mg/kg) or inulin (200 and 400 mg/kg). Serum biochemical, lipid, and cardiac injury markers were estimated. The metabolic enzyme activity (G6Pase, FBPase, ATPase, ENTPDase, 5′NT), oxidative stress markers (SOD, CAT, GSH, MDA, LDH), Angiotensin-Converting Enzyme (ACE) activity, and histological changes in the heart, pancreas, liver, and kidney, were assessed. NF-κB and Nrf2 immunohistochemistry was used to evaluate inflammatory and oxidative signalling. Treatment with inulin and cichoriin, especially at higher dosages, improved ACE activity, normalized metabolic enzyme activities, and substantially restored antioxidant enzyme levels. They reduced hyperglycemia, body weight loss, hyperlipidemia, and heart dysfunction with histological changes and fibrosis brought on by diabetes. Alongside these effects, cardiac tissues showed increased Nrf2 expression and decreased NF-κB, indicating the return of redox equilibrium and myocardial integrity. Thus, cichoriin and inulin substantially ameliorate the DCM by reducing oxidative injury, controlling glucose metabolism, and altering NF-κB/Nrf2 signaling pathways. These results demonstrate their potential for use as natural cardioprotective agents in the treatment of diabetic cardiomyopathy.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 627-645"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118382","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":"Assessment of p-phenylenediamine toxicity in subcellular compartments of hepatic and ocular tissues in Oreochromis mossambicus (Peters, 1852)","authors":"Koottasseri Amrutha,&nbsp;Kumari Chidambaran Chitra","doi":"10.1016/j.freeradbiomed.2026.01.048","DOIUrl":"10.1016/j.freeradbiomed.2026.01.048","url":null,"abstract":"<div><div>p-Phenylenediamine (p-PD), an emerging organic contaminant, poses increasing concern for aquatic ecosystems, yet its toxicological impact on fish remains inadequately addressed. This study investigated the biochemical, molecular, and histopathological alterations in the liver and eye of <em>Oreochromis mossambicus</em> exposed to a sublethal concentration (73.3 μg L⁻¹) and an environmentally relevant concentration (235.3 ng L⁻¹) of p-PD for 1, 7, 14, 30, 45, and 60 days. Exposure to p-PD significantly induced oxidative and nitrative stress in nuclear, mitochondrial, and cytosolic fractions of both tissues, as evidenced by alterations in antioxidant responses, including superoxide dismutase, glutathione reductase, glutathione peroxidase, glutathione redox ratio, total antioxidant capacity, and oxidative stress indicators such as lipid peroxidation and hydrogen peroxide formation. The transcriptional expression of <em>sod</em> and <em>gpx</em> genes further confirmed disruptions in oxidative defence mechanisms. Enhanced nitrative stress was evidenced by elevated levels of nitrate, nitrite, nitric oxide, and 3-nitrotyrosine. Besides, tissue dysfunction was indicated by significant changes in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acid phosphatase, lactate dehydrogenase, and α-fucosidase activities. Histopathological analysis revealed pronounced structural damage, including necrosis, inflammation, and marked architectural disruption in hepatic and ocular tissues. The integrated biochemical, molecular, and morphological findings demonstrate that p-PD induces considerable hepatic and ocular toxicity in <em>O. mossambicus</em>. These results underscore the ecological risk posed by p-PD and highlight the need for further investigation to support long-term environmental monitoring and regulatory measures.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 725-741"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137448","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":"2026-03-16","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":"UBR4 attenuates cisplatin-induced acute kidney injury by regulating the HRI-ISR axis","authors":"Zeyu Tang ,&nbsp;Chen Li ,&nbsp;Cheng Yang ,&nbsp;Xinghua Chen ,&nbsp;Maoqing Tian ,&nbsp;Liwen Qiao ,&nbsp;Jiefei Zeng ,&nbsp;Wenjing Zhen ,&nbsp;Wei Liang ,&nbsp;Lunzhi Liu ,&nbsp;Huiming Wang ,&nbsp;Xiangyou Li ,&nbsp;Lu Zhang","doi":"10.1016/j.freeradbiomed.2026.01.025","DOIUrl":"10.1016/j.freeradbiomed.2026.01.025","url":null,"abstract":"<div><div>Cisplatin is widely used in treating solid tumors, but its dose-limiting nephrotoxicity, which manifests as acute kidney injury (AKI), remains a major clinical challenge. The molecular pathways determining proximal tubular epithelial cell (PTEC) susceptibility during cisplatin-induced injury are not fully elucidated. Here, we identify ubiquitin protein ligase E3 component n-recognin 4 (UBR4) as a key regulator of the integrated stress response (ISR), which plays an important role in regulating reactive oxygen species (ROS) accumulation and mitophagy in the kidney. UBR4 expression was markedly upregulated in PTECs of mice with cisplatin-induced AKI. Tubule-specific <em>Ubr4</em> deficiency exacerbated kidney dysfunction, tubular damage, and cell death. Mechanistically, UBR4 promoted ubiquitination and degradation of the kinase HRI, thereby constraining ISR overactivation and alleviating its inhibitory effect on mitophagy. Consistent with this mechanism, both genetic enhancement of UBR4 and pharmacological inhibition of the ISR with ISRIB significantly mitigated cisplatin-induced nephrotoxicity. Together, our findings uncover a previously unrecognized UBR4-HRI-ISR regulatory axis that serves as an intrinsic protective mechanism in the kidney and highlight UBR4 as a promising therapeutic target for preventing cisplatin-induced tubular injury.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 269-289"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997866","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}