Free Radical Biology and Medicine最新文献

{"title":"Gut derived (S)-Equol mitigates influenza viral pneumonia by modulating macrophage polarization via Nrf2 mediated AKT/ERK/NF-κb signaling pathways.","authors":"Zheying Mao, Chang Liu, Jili Ni, Mingzhu Huang, Wenxin Qu, Weizhen Chen, Yifei Shen, Tian Qin, Meng Gao, Shufa Zheng, Yu Chen","doi":"10.1016/j.freeradbiomed.2025.08.004","DOIUrl":"10.1016/j.freeradbiomed.2025.08.004","url":null,"abstract":"<p><p>Respiratory virus including influenza A virus (IAV) infection induces alterations in gut microbiota structure and function, which in turn plays an essential role in the pathogenic process. Alterations in gut microbiota are usually accompanied with changes in metabolites. The specific relationship between dynamic changes in gut microbiota and serum metabolites in influenza remains unclear. In this study, we depicted dynamic changes in composition of gut microbiota by using metagenomic sequencing in an influenza mouse model. Through mass spectrometry based metabolomic, we identified (S)-Equol as a notable protective metabolite derived from intestinal flora. Serum (S)-Equol level decreased from the initial infection phase and increased gradually during the convalescence phase, which was positively associated with the changes in some Eggerthella and Bifidobacterium species. Antibiotic treatment reduced serum (S)-Equol level and exacerbated lung pathological damage. Oral administration of (S)-Equol relieved disease severity and controlled inflammatory infiltration. Mechanistically, (S)-Equol activated Nrf2 in macrophages, thereby inhibited AKT, ERK and NF-κB phosphorylation. The inhibition of these signaling pathways ultimately restrained pro-inflammatory cytokines release and repressed pro-inflammatory macrophage polarization. Moreover, serum (S)-Equol level was lower in influenza patients at progressed phase and was negatively correlated with serum levels of IL-6, IL-1β, and TNF-α. Collectively, our data highlighted gut derived (S)-Equol a promising postbiotic for alleviating influenza pneumonia.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"457-471"},"PeriodicalIF":8.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803934","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":"Hyperactivation of the m⁶A demethylase FTO to down-regulate SLC7A11/xCT-mediated redox homeostasis and epigenetic remodeling in facial infiltrating lipomatosis.","authors":"Hongrui Chen, Wei Gao, Zening Huang, Shih-Jen Chang, Yajing Qiu, Bin Sun, Xiaoxi Lin, Chen Hua","doi":"10.1016/j.freeradbiomed.2025.08.001","DOIUrl":"10.1016/j.freeradbiomed.2025.08.001","url":null,"abstract":"<p><p>Facial infiltrating lipomatosis (FIL) is a rare congenital disorder characterized by excessive adipose tissue accumulation and infiltration, leading to severe functional and aesthetic impairments. Current surgical interventions face high recurrence rates and complications, necessitating exploration of molecular mechanisms driving FIL. N⁶-methyladenosine (m⁶A) RNA modification plays an essential role in modulating RNA stability and contribute to the regulation of adipogenesis. However, the detailed mechanism by which m⁶A regulator regulates the pathogenesis of FIL remains unclear. We focused on FTO-mediated m⁶A demethylation and evaluated FTO expression in FIL adipose tissues and adipose stem and progenitor cells (ASPCs) using Western blotting, qPCR, immunohistochemistry, and single-cell RNA sequencing. The regulatory mechanism of FTO on SLC7A11 was explored via MeRIP-seq, RIP-qPCR, and luciferase reporter assays. In vivo effects were evaluated using xenograft, NAC gavage, and AAV8-mediated SLC7A11 overexpression models. The mechanisms by which SLC7A11 influenced adipogenesis were investigated through ATAC-seq, ChIP-qPCR, and enzyme activity assays. FTO was upregulated in FIL tissues and ASPCs, correlating with reduced m⁶A levels, enhanced adipogenesis, and disease severity. Mechanistically, FTO decreased m⁶A modification of SLC7A11, impairing IGF2BP1-mediated stabilization and reducing SLC7A11 expression. This lowered cystine uptake and GSH/GSSG ratio, inhibiting SIRT6 activity and elevating H3K9ac at promoters of adipogenic genes (PPARG, CEBPA, FABP4), thereby enhancing chromatin openness and transcriptional activation. In vivo, SLC7A11 overexpression impaired adipogenic effects. Modulating GSH/GSSG ratios via NAC or BSO validated the redox-epigenetic axis in regulating adipogenesis. Our findings collectively demonstrate that FTO drives FIL progression by m⁶A-dependent suppression of SLC7A11, disrupting redox balance and regulating SIRT6-H3K9ac-mediated epigenetic reprogramming to promote adipogenesis. Targeting the FTO/SLC7A11/GSH/SIRT6 axis offers a promising therapeutic strategy for FIL.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"432-448"},"PeriodicalIF":8.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793895","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":"NO-induced change in the oxidation state of cytochrome c in endothelial cells monitored by resonance Raman imaging.","authors":"Ewa Szczesny-Malysiak, Amanda Bartkowiak, Katarzyna Bulat, Jakub Dybas","doi":"10.1016/j.freeradbiomed.2025.08.010","DOIUrl":"10.1016/j.freeradbiomed.2025.08.010","url":null,"abstract":"<p><p>Nitric oxide (NO) is a key signalling molecule in endothelial cells, playing a complex role in the regulation of cell apoptosis. One of its critical molecular targets is cytochrome c (CytC), a heme protein whose oxidation state determines its function in mitochondrial respiration and cell death pathways. Using resonance Raman (RR) imaging with 405 nm excitation, we investigated NO-induced changes in the redox state of CytC in various endothelial cell lines. Calcium ionophore (A23187), known to activate endothelial NO synthase (eNOS), induced a shift in CytC from the ferrous (CytC-Fe^II) to ferric (CytC-Fe^III) state. This effect was cell type-dependent and most prominent in human aortic and dermal microvascular endothelial cells (HAECs, HMECs). The transition was prevented by L-NAME (NOS inhibitor), PEG-SOD (superoxide scavenger), and NecroX-5 (peroxynitrite scavenger), suggesting that ONOO^- plays a mediating role. Physiological NO inducers like VEGF and bradykinin also promoted CytC oxidation, but in a spatially distinct manner, suggesting subcellular specificity in NO signalling. Interestingly, applying an external NO donor (DEA-NONOate) did not trigger oxidation but briefly formed a CytC-Fe^II-NO complex. Despite mitochondrial membrane potential disturbances following A23187 treatment, no apoptosis was observed, indicating that CytC oxidation can be an early, reversible marker of mitochondrial stress rather than cell death. Our findings demonstrate the utility of RR imaging for real-time monitoring of CytC redox state and underscore the complexity of NO signalling in endothelial physiology and its potential implications for vascular health.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"472-482"},"PeriodicalIF":8.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811926","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":"Dehydroascorbic acid impairs neurite growth through RIPK1-associated caspase activation.","authors":"Rocío Magdalena, Luciano Ferrada, Eder Ramírez, Javiera Fernanda Smith-Ghigliotto, Katterine Salazar, Francisco Nualart","doi":"10.1016/j.freeradbiomed.2025.07.036","DOIUrl":"10.1016/j.freeradbiomed.2025.07.036","url":null,"abstract":"<p><p>Axonal and neurite loss is a common event in neurodegenerative diseases, such as Alzheimer's disease or amyotrophic lateral sclerosis, which are enhanced by oxidative damage and reactive oxygen species (ROS) production. In the central nervous system, vitamin C can be found as ascorbic acid (AA), its reduced form, or dehydroascorbic acid (DHA), its oxidized form. Vitamin C mainly acts as an antioxidant agent, and homeostasis in the brain is maintained through its recycling between neurons and astrocytes. However, DHA accumulation under pathophysiological conditions has been associated with changes in neuronal metabolism and necroptotic cell death through RIPK1 activation. Furthermore, recent studies show that DHA accumulation induces significant neurite loss; however, it is unknown whether this effect is associated with RIPK1 activation. Here, we show that DHA treatment on neurospheres (NE) in vitro induces significant neurite shortening and reduced branching, effects associated with early RIPK1 activation and inhibited through Necrostatin-1s and zVAD-FMK treatment, suggesting the activation of apoptotic mechanisms. Finally, we propose DHA, the oxidized form of vitamin C, impairs neurite growth through ripk1-associated caspase activation.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"406-416"},"PeriodicalIF":8.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741791","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":"Porcine epidemic diarrhea virus induces PANoptosis in piglet intestinal cells via Z-RNA/ZBP1/ROS pathway-mediated oxidative stress activation.","authors":"Xin-Yue Sun, Jing Wang, Wen-Jun Tian, Yan-Ru Zhang, Yin-Long Zhang, Yun-Long Shi, Ran-Ran Gong, Si-Nong Wu, Hong-Yu Qu, Xiao-Jia Wang","doi":"10.1016/j.freeradbiomed.2025.07.037","DOIUrl":"10.1016/j.freeradbiomed.2025.07.037","url":null,"abstract":"<p><p>Porcine epidemic diarrhea virus (PEDV) is a type of coronavirus that infects pigs, resulting in high mortality rates in piglets and posing a significant threat to the swine industry. However, the biological mechanisms underlying PEDV-induced intestinal damage and the role of oxidative stress in this context remain poorly understood. In the present study, quantitative proteomics was employed to identify key genes associated with PEDV infection. We established an in vivo PEDV infection model using piglets and conducted in vitro studies employing Z-nucleic acid (NA)-binding protein 1 (ZBP1) knockdown and knockout (KO) models in Vero E6 cells. Several techniques were used, including transmission electron microscopy, H&E staining, confocal laser scanning microscopy, TUNEL staining, and AO/EB staining, to assess morphological changes in the intestinal tissue of piglets and to evaluate alterations in oxidative stress, mitochondrial membrane potential, and PANoptosis-related marker molecules in cells. Our findings indicated that PEDV infection results in increased expression of ZBP1 and PANoptosis-related markers. In vitro experiments demonstrated that PEDV-N colocalizes with Z-RNA and ZBP1, and that oxidative stress inhibitors effectively mitigate PEDV-induced PANoptosis. Collectively, our results suggest that ZBP1 triggers cellular oxidative damage by recognizing Z-NA structures during PEDV invasion, thereby inducing apoptosis, pyroptosis, and necroptosis, which ultimately leads to intestinal PANoptosis. These findings provide a theoretical framework for understanding PEDV-induced intestinal injury in piglets and offer valuable insights for comparative medicine research.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"386-405"},"PeriodicalIF":8.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775014","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":"Lipoprotein disruption following ischemic stroke across subtypes and over time: Findings from NMR-based metabolomic analysis.","authors":"Amy May Lin Quek, Ooiean Teng, Ju-Hea Park, Bernadette Guek Cheng Er, Erle Chuen Hian Lim, Raymond Chee Seong Seet","doi":"10.1016/j.freeradbiomed.2025.07.041","DOIUrl":"10.1016/j.freeradbiomed.2025.07.041","url":null,"abstract":"<p><p>Despite rising stroke rates, we still lack reliable blood biomarkers to elucidate mechanisms, refine subtypes, and track recovery. We investigated whether high-throughput nuclear magnetic resonance (NMR) spectroscopy, including lipid-ratio metrics, could uncover pathway disruptions across stroke subtypes and over six months. Between October 2018 and July 2019, we recruited acute ischemic stroke patients and age-matched healthy controls. We quantified metabolites and ratio-based measures using NMR. Univariate tests and multivariable logistic regression (adjusting for relevant covariates) were employed to (1) compare ischemic stroke versus controls, (2) delineate subtype-specific differences, and (3) evaluate longitudinal biomarker changes. Overall, 523 stroke patients (mean age 57.4 years) and 203 controls were enrolled; 72 stroke patients provided follow-up samples at 6 months. Compared with controls, stroke patients showed elevated cholesteryl esters in intermediate-density lipoproteins (IDL), triglycerides in large and medium high-density lipoprotein (HDL), and cholesterol in IDL (all p < 0.05), alongside lower acetone, acetoacetate, and HDL-related measures. Stroke subtype analyses revealed particularly atherogenic lipid profiles in large artery disease (increased IDL cholesteryl esters, large HDL triglycerides); pronounced pyruvate and very small very-low-density lipoprotein (VLDL) disruptions in cardioembolism; and marked IDL/HDL abnormalities in lacunar stroke. Over six months, stroke survivors exhibited significant metabolic shifts, with increased glycine and the triglycerides-to-total-lipids ratios in medium, large, and small LDL six months following an ischemic stroke. However, these biomarker elevations did not correlate with functional recovery. NMR revealed stroke-specific lipid/ketone signatures, mapped stroke subtypes, and tracked recovery remodeling, yielding actionable prognostic biomarkers.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"449-456"},"PeriodicalIF":8.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783924","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":"Temporal dynamics of oxylipins and antioxidant metabolites in rainbow trout muscle are driven by diet type rather than methylmercury or selenomethionine supplementation.","authors":"Marius Bidon, Cécile Heraud, Claudia Marchán-Moreno, Laurence Larroquet, Guillaume Reversat, Claire Vigor, Camille Oger, Jean-Marie Galano, Thierry Durand, Zoyne Pedrero-Zayas, Stéphanie Fontagné-Dicharry, Jérôme Roy","doi":"10.1016/j.freeradbiomed.2025.07.043","DOIUrl":"10.1016/j.freeradbiomed.2025.07.043","url":null,"abstract":"<p><p>Tuna by-products in aquafeed pose challenges due to heavy metals like mercury (Hg), which has pro-oxidant effects. However, they also contain selenium (Se), an antioxidant oligoelement. This study assessed the oxidative impact of these elements in juvenile rainbow trout over a 6-month feeding trial. Fish were fed plant-based or tuna-based diets, with or without supplementation of methylmercury (MeHg) and selenomethionine (SeMet). Muscle samples were collected at 0, 21, 84, and 168 days to analyze fatty acid profiles, non-enzymatic oxylipins, and antioxidant metabolites (glutathione, vitamin E). Tuna-fed fish exhibited higher oxylipin levels and lower antioxidant metabolites compared to plant-fed fish. Notably, oxylipin levels remained elevated at 84 and 168 days in tuna-fed fish, correlating with a decrease in the GSH:GSSG ratio. In contrast, plant-fed fish showed a transient increase in oxylipins at 84 days, which normalized by day 168, aligning with a temporary drop in the GSH:GSSG ratio. MeHg and SeMet supplementation did not alter these trends. Surprisingly, these findings, along with a previous study, suggest that prolonged oxidative stress in tuna-fed fish is more closely linked to Se bioaccumulation than Hg. Future work should investigate dietary Se concentration and form to better understand these results.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"417-431"},"PeriodicalIF":8.2,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768586","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":"Turning Off the Ferroptosis Switch: ACAA1-Driven PI3K/AKT/Nrf2 Signaling as a Novel Driver of Endometrial Cancer Progression.","authors":"Tingyu Lang, Peichen Xiao, Shaoqi Hua, Xiaolei Liang, Yongxiu Yang","doi":"10.1016/j.freeradbiomed.2025.09.054","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.09.054","url":null,"abstract":"<p><p>Endometrial carcinoma (EC) is a prevalent gynecologic malignancy with rising global incidence. Dysregulated lipid metabolism promotes EC progression through estrogen synthesis, metabolic reprogramming, and tumor microenvironment remodeling. Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, represents a potential therapeutic strategy, yet its resistance mechanisms in EC remain unclear. We identify Acetyl-CoA Acetyltransferase 1 (ACAA1), a key enzyme in mitochondrial fatty acid β-oxidation, as an oncogenic factor in EC. We demonstrate that ACAA1 is significantly upregulated in EC tissues via bioinformatic analysis and clinical samples. Functionally, ACAA1 overexpression enhances tumor cell proliferation, migration, energy metabolism, and lipid droplet synthesis in vitro, while accelerating tumor growth in vivo in xenograft models. Mechanistically, ACAA1 activates the PI3K/AKT pathway, leading to nuclear translocation of the transcription factor Nrf2. This ACAA1/PI3K/AKT/Nrf2 axis suppresses ferroptosis by regulating redox homeostasis and lipid peroxidation, thereby promoting EC progression. Our findings reveal ACAA1 as a novel regulator of ferroptosis resistance and tumorigenesis in EC, highlighting its potential as a promising therapeutic target for EC treatment.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238431","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":"Acrolein-induced PKM2 modification drives NETosis and glioma progression.","authors":"Hsiang-Tsui Wang, Zhen-Jie Tong, Ya-Rou Lin, Kuo-Chen Wei, Chiung-Yin Huang, Pin-Yuan Chen, Ko-Ting Chen, Ya-Jui Lin, Hong-Chieh Tsai","doi":"10.1016/j.freeradbiomed.2025.10.006","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.10.006","url":null,"abstract":"<p><p>Glioblastoma, the most common and aggressive primary brain tumor, is characterized by profound hypoxia and treatment resistance. Hypoxia drives lipid peroxidation, producing acrolein, a reactive aldehyde that induces DNA damage, mitochondrial dysfunction, and oxidative stress. Neutrophils, through a process known as NETosis, release neutrophil extracellular traps (NETs), which have been linked to tumor progression and a poor prognosis. Here, we identify acrolein as a key regulator of NETosis in glioma. Transcriptomic profiling of peripheral neutrophils from glioma patients revealed upregulated NET-associated pathways, consistent with elevated NET formation and reduced survival. NET levels correlated positively with acrolein accumulation in plasma and tumor tissues. Mechanistically, hypoxia-induced acrolein production in glioma cells promoted NETosis in co-cultured neutrophils, thereby enhancing tumor cell proliferation and migration. Acrolein modified PKM2 at Cys326 and Cys358, inducing its nuclear translocation and co-activation of HIF-1α, which in turn upregulated the expression of IL-6 and IL-8. Pharmacologic activation of PKM2 with TEPP-46 blocked acrolein-induced nuclear PKM2 translocation, reduced NET formation in vitro, and suppressed tumor growth and NET levels in vivo. The acrolein scavenger hydralazine also inhibited NETosis in vitro and both subcutaneous and orthotopic glioma models. These findings define an acrolein-PKM2-NET axis in glioblastoma, highlighting NETosis inhibition as a potential therapeutic approach.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238408","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":"Isoliquiritigenin attenuates cisplatin-induced hearing loss and ototoxicity by activating the Keap1-Nrf2-ARE pathway.","authors":"Ying Chen, Xiaoyang Luo, Yanyan Deng, Guanghao Zhu, Xiayan Chu, Jingjing Zhu, Siyi Shao, Lijun Zhang, Xiang Chen, Yuqing Chen, Chang Lin, Guangbo Ge, Shuhui Wu","doi":"10.1016/j.freeradbiomed.2025.10.004","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.10.004","url":null,"abstract":"<p><p>Cisplatin-induced hearing loss (CIHL), a major dose-limiting toxicity of cisplatin, is primarily caused by oxidative stress and apoptosis in cochlear hair cells. This study aims to investigate the otoprotective effects of Isoliquiritigenin (ISL, a natural Nrf2 agonist) on CIHL and to elucidate the underlying anti-CIHL mechanism(s) of ISL. Initially, ISL was identified as a natural Nrf2 agonist from a phytochemical library using a luciferase reporter gene system. The otoprotective effects of ISL were then investigated in HEI-OC1 cells, cochlear explants, and in cisplatin-induced ototoxicity murine models. In cisplatin-induced ototoxicity mice, ISL markedly restored full-frequency auditory brainstem response (ABR) thresholds and attenuated cisplatin-induced hair cell loss in the cochlea. In HEI-OC1 cells and cochlear explants, ISL significantly attenuated cisplatin-triggered reactive oxygen species (ROS) overproduction, mitochondrial dysfunction, and hair cell apoptosis. Mechanistically, ISL covalently modify two critical cysteine residues (Cys226 and Cys288) of KEAP1, which subsequently stabilized Nrf2 and upregulated the expression of downstream antioxidant proteins including NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1) and superoxide Dismutase (SOD). Collectively, our findings clearly demonstrate that ISL significantly attenuates cisplatin-induced hearing loss (CIHL) by activating the Keap1-Nrf2-ARE signaling via covalent modifying two key cysteine residues on KEAP1.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231868","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}