Free Radical Biology and Medicine最新文献

{"title":"Circulating Neuregulin-4 tracks acute hyperbaric and workload stress in human divers, preceding oxidative injury markers","authors":"Claudia Di Biagio ,&nbsp;Paola Giglio ,&nbsp;Matteo Bordi ,&nbsp;Giovanni Larotondo ,&nbsp;Riccardo Turchi ,&nbsp;Luigi Fattorini ,&nbsp;Enrico Marchetti ,&nbsp;Daniele Lettieri-Barbato ,&nbsp;Costanza Montagna ,&nbsp;Giuseppe Filomeni ,&nbsp;Katia Aquilano","doi":"10.1016/j.freeradbiomed.2026.02.002","DOIUrl":"10.1016/j.freeradbiomed.2026.02.002","url":null,"abstract":"<div><div>Acute hyperbaric stress during diving combines increased ambient pressure, hyperoxia, hemodynamic shifts, and often muscular workload. Identifying real-time blood biomarkers sensitive to these individual and combined physiological loads remains a challenge. Neuregulin-4 (NRG4), an adipokine secreted by thermogenic and subcutaneous white fat, responds to adrenergic stimulation and modulates redox homeostasis. We investigated NRG4 dynamics alongside oxidative protein carbonyls in divers in warm (thermoneutral) water (∼33.6 °C ambient water temperature) to avoid cold stress.</div><div>Two field campaigns were conducted: a first depth response campaign involved divers exposed to 20, 30, or 40 m on separate days, without exercise, with serial blood sampling; a second physical effort study involved 15 m dives with or without slow-pedalling exercise. Serum NRG4 was quantified by ELISA and expressed as log₂ fold change relative to baseline. Protein carbonyls were measured as markers of oxidative damage. Statistical analysis employed single-sample tests and false-discovery rate control.</div><div>NRG4 exhibited a robust early increase at 30 m, significant after correction, and nominal elevations at 40 m, but remained unchanged at 20 m. Exercise at 15 m triggered a significant early NRG4 rise absent during passive dives at the same depth. Protein carbonyls remained stable in early post-emersion windows but increased significantly at later time points (180- and 240-min post-emersion) following dives to 40 m, indicating delayed oxidative burden.</div><div>Our findings position NRG4 as a fast, pressure- and workload-responsive biomarker of diving stress, temporally distinct from classical oxidative injury markers that manifest later. This temporal dissociation underscores the potential of NRG4 for real-time monitoring of acute physiological load during hyperbaric exposure, integrating pressure- and workload-related stressors.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 660-667"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118434","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 “NEAT1/hsa-miR-372–3p axis participates in rapamycin-induced lipid metabolic disorder” [Free Radic. Biol. Med. 167 (2021) 1-11]","authors":"Guanghan Fan ,&nbsp;Chenzhi Zhang ,&nbsp;Xuyong Wei ,&nbsp;Rongli Wei ,&nbsp;Zhetuo Qi ,&nbsp;Kangchen Chen ,&nbsp;Xuechun Cai ,&nbsp;Li Xu ,&nbsp;Linsong Tang ,&nbsp;Junbin Zhou ,&nbsp;Zhensheng Zhang ,&nbsp;Zuyuan Lin ,&nbsp;Haiyang Xie ,&nbsp;Shusen Zheng ,&nbsp;Weimin Fan ,&nbsp;Xiao Xu","doi":"10.1016/j.freeradbiomed.2026.02.022","DOIUrl":"10.1016/j.freeradbiomed.2026.02.022","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Page 796"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197544","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 cysteinyl-tRNA synthetase 2 protects against excitotoxic retinal cell death via enhanced supersulfide production","authors":"Yuri Chida ,&nbsp;Risa Shiokawa ,&nbsp;Hiroshi Tawarayama ,&nbsp;Minami Takeda ,&nbsp;Hirokazu Hasegawa ,&nbsp;Naoki Takahashi ,&nbsp;Hiroshi Kunikata ,&nbsp;Takaaki Akaike ,&nbsp;Toru Nakazawa","doi":"10.1016/j.freeradbiomed.2026.01.009","DOIUrl":"10.1016/j.freeradbiomed.2026.01.009","url":null,"abstract":"<div><div>Mitochondrial cysteinyl-transfer RNA synthetase 2 (CARS2) is involved not only in the ligation of cysteine to transfer RNA but also in the synthesis of intracellular supersulfides. In this study, we investigated the role of CARS2 in the survival of retinal ganglion cells (RGCs) under excitotoxic conditions.</div><div>Immunohistochemical analysis showed strong expression of CARS2 in RBPMS-positive RGCs in the mouse retina. Overexpression of exogenous human CARS2 (hCARS2) in mouse retinas and in the rat-derived retinal cell line R28 did not affect endogenous CARS2 mRNA levels. Adeno-associated virus 2-mediated overexpression of hCARS2 in RGCs significantly reduced cell death induced by excitotoxicity following intravitreal injection of N-methyl-D-aspartate. Similarly, hCARS2 overexpression decreased glutamate-induced excitotoxic cell death in R28 cells. Quantitative reverse transcription polymerase chain reaction analysis demonstrated a significant increase in CARS2 expression in R28 cells treated with glutamate. Using specific probes, we found that hCARS2-overexpressing R28 cells treated with glutamate exhibited higher intracellular levels of sulfane sulfur species and lower levels of reactive oxygen species (ROS) than control cells with basal CARS2 expression. Moreover, the oxidative stress marker gene Hmox1 was significantly downregulated in CARS2-overexpressing R28 cells compared with control cells.</div><div>Taken together, these findings suggest that CARS2 plays a critical role in protecting retinal cells from excitotoxic cell death by increasing sulfane sulfur production and decreasing ROS accumulation. Given that CARS2 is predominantly expressed in RGCs among retinal cells, it may serve as a preemptive defense mechanism that enhances antioxidative activity at basal expression levels to support RGC survival.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 69-79"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932896","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":"Protein S-sulfhydration: Mechanisms and therapeutic implications in Alzheimer's disease and Parkinson's disease","authors":"Jinfen Guo ,&nbsp;Changku Shi ,&nbsp;Chunyu Yu ,&nbsp;Yu Wang ,&nbsp;Maotao He","doi":"10.1016/j.freeradbiomed.2026.01.033","DOIUrl":"10.1016/j.freeradbiomed.2026.01.033","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases have complex pathogenic mechanisms. Traditional theories (e.g., free radical damage/oxidative stress, inflammatory responses) have laid a foundation for understanding these pathological processes. However, single mechanisms cannot fully explain their complexity. In recent years, post-translational modifications (PTMs)—especially redox-related types such as S-sulfhydration—have emerged as key complementary regulators of nervous system homeostasis and disease progression. It is mediated by the endogenous gas signaling molecule hydrogen sulfide (H₂S) and has unique regulatory effects.</div></div><div><h3>Aim of review</h3><div>This review systematically summarizes the molecular mechanisms and therapeutic targets of S-sulfhydration in AD and PD. It discusses the potential of S-sulfhydration in disease intervention and treatment. It also looks into H₂S-based therapeutic strategies and their clinical application prospects. This review aims to provide a theoretical basis for understanding the role of PTMs in neurological diseases.</div></div><div><h3>Key scientific concepts of review</h3><div>This review summarizes clearly: in AD and PD, S-sulfhydration interacts with protein modifications like phosphorylation, S-nitrosylation and succinylation. It regulates key pathogenic proteins such as Tau, Aβ and Parkin. It also takes part in regulating energy metabolism, resisting oxidative stress and inhibiting inflammatory responses. These effects influence neuronal survival and functional homeostasis. This indicates that S-sulfhydration plays an important regulatory role in AD and PD progression. It is part of the complex network of pathological mechanisms. Its modification mechanisms and interaction pathways offer promising complementary molecular targets and intervention strategies for treating AD, PD, and other potential neurodegenerative diseases.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 431-441"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029073","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":"Nsun2-mediated m5C methylation of Ncor1 exacerbates sepsis-induced cardiomyopathy by promoting mitochondrial dysfunction","authors":"Chan Chen,&nbsp;Qing Liu,&nbsp;Junmei Xu,&nbsp;Mengyuan Zi,&nbsp;Xinglan Chen,&nbsp;Feng Xiao","doi":"10.1016/j.freeradbiomed.2025.12.056","DOIUrl":"10.1016/j.freeradbiomed.2025.12.056","url":null,"abstract":"<div><div>Sepsis-induced cardiomyopathy (SIC) is a severe complication of sepsis characterized by mitochondrial dysfunction and impaired myocardial contractility, yet its molecular pathogenesis remains incompletely understood. In this study, we demonstrate that excessive mitochondrial fission plays a pivotal role in SIC, contributing to inflammation, oxidative stress, and cardiomyocyte apoptosis. Pharmacological inhibition of mitochondrial fission using Mdivi-1 alleviated these pathological changes both in vivo and in vitro. Bioinformatic analyses of public datasets identified nuclear receptor corepressor 1 (Ncor1) as a key mitochondrial dynamics-related gene upregulated in SIC. Lentiviral knockdown of Ncor1 mitigated myocardial injury and restored mitochondrial homeostasis in both lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) induced SIC mouse model. Mechanistically, we found that the RNA m5C methyltransferase Nsun2 was significantly upregulated in SIC and enhanced Ncor1 mRNA stability via m5C methylation through reading protein ALYREF. Functional experiments revealed that Nsun2 knockdown ameliorated cardiomyocyte injury, while co-knockdown of Ncor1 reversed the deleterious effects of Nsun2 overexpression. Collectively, our findings reveal a novel Nsun2/Ncor1 axis that drives mitochondrial dysfunction in SIC through epitranscriptomic regulation, providing potential therapeutic targets for septic cardiac injury.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 17-34"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888827","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":"Fyn deficiency drives pro-inflammatory macrophage activation to exacerbate septic acute lung injury","authors":"Yi Liu ,&nbsp;Bangjun Xu ,&nbsp;Wuxiong Zhang ,&nbsp;Yifan Zuo ,&nbsp;Tinglv Fu ,&nbsp;Xiao Lu ,&nbsp;Xin Xing ,&nbsp;Qing Geng ,&nbsp;Bohao Liu ,&nbsp;Ning Li ,&nbsp;Qingsong Ye","doi":"10.1016/j.freeradbiomed.2025.12.022","DOIUrl":"10.1016/j.freeradbiomed.2025.12.022","url":null,"abstract":"<div><div>Macrophage-driven inflammation is a hallmark of sepsis-associated acute lung injury (ALI). Fyn, a Src family kinase, plays a pivotal role in diverse cellular signaling pathways. While prior studies established that Toll-like receptor (TLR) activation rapidly initiates Fyn activation, its precise immunoregulatory functions and role in sepsis-induced ALI remain contentious. In this study, we investigated the impact of Fyn deficiency on cecal ligation and puncture (CLP)-induced septic ALI. Furthermore, we utilized murine bone marrow-derived macrophages (BMDMs) and human THP-1-derived macrophages to elucidate the influence of Fyn on macrophage inflammatory responses. Fyn deficiency significantly exacerbated pulmonary inflammation and injury in ALI mice, as evidenced by histopathological analysis of lung tissue, elevated cytokine levels, and reduced survival. Notably, Fyn deficiency potentiated macrophage inflammatory responses. This effect was mediated through the suppression of TNF receptor-associated factor 6 (TRAF6) ubiquitination and degradation, thereby augmenting TLR4-NF-κB signaling. Consequently, Fyn deficiency led to excessive macrophage cytokine production and exacerbated ALI severity. Collectively, these findings underscore Fyn as a critical immunomodulator and highlight its potential as a therapeutic target for immunomodulation and anti-inflammatory strategies in sepsis-induced ALI and related acute inflammatory disorders.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 80-92"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905886","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":"TRIM28 aggravates myocardial infarction-induced cardiomyocyte apoptosis through regulating the stability of ATF5 via ubiquitination and SUMOylation","authors":"Yanying Wang ,&nbsp;Mingyu Yang ,&nbsp;Junting Ren ,&nbsp;Wei Liu ,&nbsp;Han Sun ,&nbsp;Guangze Wang ,&nbsp;Siyu Wang ,&nbsp;Ying Zhang ,&nbsp;Haodong Li ,&nbsp;Dongping Liu ,&nbsp;Mengmeng Li ,&nbsp;Yanwei Zhang ,&nbsp;Hao Wang ,&nbsp;Xuewen Yang ,&nbsp;Xiyang Zhang ,&nbsp;Yuhan Liu ,&nbsp;Lei Jiao ,&nbsp;Lihua Sun ,&nbsp;Lina Xuan ,&nbsp;Xuelian Li ,&nbsp;Ying Zhang","doi":"10.1016/j.freeradbiomed.2026.01.055","DOIUrl":"10.1016/j.freeradbiomed.2026.01.055","url":null,"abstract":"<div><div>Myocardial infarction (MI) stands as a leading contributor to global cardiovascular morbidity and mortality, defined by ischemic myocardial cell death and subsequent impairment of cardiac function. The tripartite motif (TRIM) protein family has been shown to regulate myocardial ischemia-reperfusion injury. As a key member of the TRIM protein family, tripartite motif-containing protein 28 (TRIM28) exhibits dysregulated expression in the heart during MI yet its pathophysiological role remains to be fully elucidated. This study aimed to investigate the functional roles and underlying mechanisms of TRIM28 in MI. We observed a significant upregulation of TRIM28 in ischemic myocardium and hypoxic cardiomyocytes. Genetic knockout of TRIM28 ameliorated cardiac function and attenuated apoptosis in MI mice, whereas its overexpression exacerbated contractile dysfunction, and promoted cardiomyocyte apoptosis and mitochondrial injury. Mechanistically, TRIM28 directly interacts with activating transcription factor 5 (ATF5) and suppresses its SUMOylation, thereby enhancing the ubiquitin-mediated degradation of ATF5, inhibiting the mitochondrial unfolded protein response (UPRmt), and ultimately culminating in increased apoptosis. Via molecular docking, we identified a TRIM28-targeting compound, Oolonghomobisflavan B (OFB), which attenuated post-MI apoptosis and facilitated cardiac function recovery. Collectively, these findings demonstrate that TRIM28 acts as a critical regulator of MI progression, and OFB holds therapeutic potential as a candidate drug.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 598-613"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096842","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":"Acetate ameliorates glucolipid metabolic dysregulation and neuroinflammation in diabetic cognitive impairment via enhanced mitophagy","authors":"Jie Zheng ,&nbsp;Yu An ,&nbsp;Xin Zhang ,&nbsp;Zhaoming Cao ,&nbsp;Guangyi Xu ,&nbsp;Jing Li ,&nbsp;Jingya Wang ,&nbsp;Li Chen ,&nbsp;Yanhui Lu","doi":"10.1016/j.freeradbiomed.2026.01.041","DOIUrl":"10.1016/j.freeradbiomed.2026.01.041","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic cognitive impairment (DCI) is an increasingly recognized complication of type 2 diabetes mellitus (T2DM) with limited effective therapies. Short-chain fatty acids (SCFAs) have been implicated in metabolic regulation and neuronal health, yet comparisons of acetate, propionate, butyrate, and their mixture are limited, and the mechanisms underlying neuroprotection in DCI remain insufficiently clarified.</div></div><div><h3>Methods</h3><div>Ninety participants (healthy controls, T2DM, and DCI groups) were assessed for serum SCFA levels and cognitive performance using the Montreal Cognitive Assessment (MoCA). In parallel, a DCI mouse model established by a 24-week high-fat diet received 8-week supplementation with acetate, propionate, butyrate, or a mixture of the three. Glucolipid metabolism, spatial learning and memory, hippocampal neuronal damage, neuroinflammation, and mitophagy were evaluated. Based on consistency across the clinical and animal datasets, acetate was selected for mitophagy-focused mechanistic experiments, and pathway dependence was examined by co-administration of the autophagy inhibitor 3-methyladenine (3-MA).</div></div><div><h3>Results</h3><div>Clinically, serum acetate, propionate, and butyrate were lower in T2DM and DCI than in healthy controls; only acetate showed a further significant reduction in DCI compared with T2DM. All three SCFAs were positively associated with MoCA score and inversely associated with fasting blood glucose, whereas acetate additionally showed inverse associations with lipid parameters. In mice, SCFA supplementation alleviated metabolic dysfunction, spatial learning and memory, neuronal loss, and neuroinflammation, with acetate generally producing more consistent and numerically greater improvements across these endpoints. Mechanistically, acetate enhanced hippocampal mitophagy by restoring LC3–TOMM20 colocalization and activating the PINK1/Parkin pathway. Importantly, 3-MA partially attenuated these benefits, indicating a mitophagy-dependent mechanism.</div></div><div><h3>Conclusions</h3><div>These integrated clinical and experimental data support a “SCFAs–mitophagy–neuroinflammation” axis linking systemic metabolism to neuronal vulnerability in DCI, and identify acetate as a promising SCFA that may enhance neuronal resilience through mitophagy activation.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 580-597"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100175","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":"YTHDF2–m6A regulation of DHRS3 at LRAT-organized organelle contacts orchestrates redox to drive radioresistance in esophageal squamous cell carcinoma","authors":"Xiaoli Lv ,&nbsp;Zhenyan Li ,&nbsp;Qiliang Peng ,&nbsp;Zhichao Fu ,&nbsp;Chao Xu ,&nbsp;Jian Wang ,&nbsp;Songbing Qin ,&nbsp;Jianping Cao ,&nbsp;Lili Wang ,&nbsp;Yang Jiao","doi":"10.1016/j.freeradbiomed.2026.01.026","DOIUrl":"10.1016/j.freeradbiomed.2026.01.026","url":null,"abstract":"<div><div>Radioresistance in esophageal squamous cell carcinoma limits the benefit of radiotherapy. The role of N6 methyladenosine readers in this phenotype remains incompletely defined. We identify a YTHDF2 centered mechanism that links RNA modification to organelle redox control. Analyses of public transcriptomes and an immunohistochemistry cohort showed that higher YTHDF2 expression associates with unfavorable outcomes after radiotherapy, and ionizing radiation transiently increases YTHDF2 in cell models. Loss of YTHDF2 sensitized esophageal squamous cell carcinoma cells to irradiation, with more apoptosis, DNA damage, reactive oxygen species, and reduced clonogenic survival. YTHDF2 overexpression conferred protection <em>in vitro</em> and preserved tumor growth in xenografts after irradiation. Integrated MeRIP-seq and MeRIP-qPCR, together with reporter assays, indicated that YTHDF2 recognizes an m⁶A-modified site within the DHRS3 3′ untranslated region and is required to maintain DHRS3 protein expression after irradiation. DHRS3 depletion phenocopied radiosensitization, elevated reactive oxygen species, and disrupted redox balance with altered NADP⁺ to nicotinamide adenine dinucleotide phosphate (NADPH) ratios, and abrogated the radioprotective effects of YTHDF2 overexpression. Spatial imaging and perturbation analyses suggested that lecithin retinol acyltransferase (LRAT) enriches DHRS3 at endoplasmic-reticulum–lipid-droplet regions juxtaposed to mitochondria after irradiation. LRAT loss dispersed these interfaces, mislocalized DHRS3, and impaired retinoid and NADPH buffering, whereas enforced mitochondrial targeting of DHRS3 partially restored redox control. Collectively, these findings support a model in which an irradiation-responsive YTHDF2–DHRS3–LRAT axis assembles a retinoid-coupled NADPH module at endoplasmic reticulum (ER)–lipid-droplet (LD)–mitochondria interfaces to limit oxidative stress and contribute to radioresistance. Mechanistic experiments illustrate how this pathway buffers irradiation-induced oxidative stress across transcriptomic, biochemical, and imaging readouts, suggesting that targeting YTHDF2 or the DHRS3–LRAT node may offer a tractable strategy to improve radiotherapy in esophageal squamous cell carcinoma.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 290-304"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024594","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":"Exercise and functional integrity in non-disease and disease states during human ageing: the relevance of VO2max","authors":"Norman R. Lazarus,&nbsp;Stephen D.R. Harridge","doi":"10.1016/j.freeradbiomed.2025.11.043","DOIUrl":"10.1016/j.freeradbiomed.2025.11.043","url":null,"abstract":"<div><div>Maximal oxygen update (VO_2max) is the acknowledged biomarker for cardiorespiratory fitness and global physiological function. It is affected by levels of exercise/physical activity and declines with increasing age even in older exercisers. Here in this conceptual paper we suggest that exercise can facilitate age-appropriate VO_2max levels across a spectrum of physiological phenotypes ranging from disease-free, through minor to more major diseases. The absence of disease during ageing is rare and requires a lifestyle of physical activity, mental wellbeing, a well-balanced nutritious diet, whilst maintaining a body weight appropriate to sex and age. The maintenance of optimal, age-adjusted function over a lifetime should be viewed as an ordered, integrated decline in physiological processes. However, in the absence of this lifestyle, patho-physiological processes take over and the end result is inevitably a lifestyle disease. Disease processes during ageing can be generally divided into those that arise largely because of lifestyle (e.g. cardiovascular disease, obesity and type 2 diabetes) and those that relate to other causes (genetics, environment etc.). If, in either situation cardio-respiratory fitness can be preserved either by exercise alone or in combination with medical interventions, then function, optimal for age, should be maintained. This article discusses concepts pertaining to exercise, optimal physiological function as reflected in the biomarker VO_2max, as well as the interplay with ROS in the presence of non-disease and disease states during ageing.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 305-315"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582064","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}