Free Radical Biology and Medicine最新文献

{"title":"Iron-oxide nanoparticles selectively enhance the toxicity of pharmacological ascorbate through hydrogen peroxide-dependent DNA damage in non-small cell lung cancer (NSCLC)","authors":"Mekhla Singhania,&nbsp;Sei Sho,&nbsp;Melissa A. Fath,&nbsp;Adriana Sanchez,&nbsp;Casey F. Pulliam,&nbsp;Bryan G. Allen,&nbsp;Garry R. Buettner,&nbsp;Prabhat C. Goswami,&nbsp;Maria Spies,&nbsp;Michael S. Petronek,&nbsp;Douglas R. Spitz","doi":"10.1016/j.freeradbiomed.2025.09.013","DOIUrl":"10.1016/j.freeradbiomed.2025.09.013","url":null,"abstract":"<div><div>Pharmacological ascorbate (IV delivery, to plasma levels ≈ 15–20 mM) has been shown to be selectively toxic to cancer vs. normal cells as well as inducing radio-chemo-sensitization in non-small cell lung cancer (NSCLC) via increased generation of hydrogen peroxide (H₂O₂) and increased intracellular redox-active iron (Fe²⁺). The current study shows that 24 h pretreatment with an FDA-approved iron-oxide nanoparticle, Ferumoxytol (FMX), enhances the toxicity of P-AscH<strong>^-</strong> in human NSCLC cells (H1299T and A549), but not in primary human bronchiolar epithelial cells (HBEpC). In H1299TCat15 cells engineered to overexpress doxycycline inducible catalase, FMX + P-AscH<strong>^-</strong> also induced cell killing and carboplatin-induced radio-chemo-sensitization that was inhibited by exposure to doxycycline, demonstrating the dependence of the biological effects on H₂O₂. P-AscH^- + FMX induced increases in intracellular redox active Fe²⁺ in H1299TCat15 cells, that was partially inhibited by doxycycline-inducible catalase overexpression, demonstrating that both P-AscH^- and H₂O₂ participate in the intracellular release of redox active Fe²⁺ from FMX. Finally, H1299TCat15 cells treated with P-AscH^- + FMX demonstrated increased single- and double-strand DNA damage, that was not seen in HBEpCs and was inhibited by doxycycline induced expression of catalase. This study represents the first demonstration that FMX combined with P-AscH<strong>^-</strong> selectively sensitize NSCLC cells (relative to normal cells) to ascorbate toxicity and chemo-radio-sensitization through enhancing H₂O₂-dependent DNA damage, that is accompanied by increased release of intracellular Fe²⁺. These results support the hypothesis that FMX can be used to selectively enhance therapy responses to P-AscH<strong>^-</strong> in NSCLC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 32-41"},"PeriodicalIF":8.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039438","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":"CRABS-ROC, A respirometry protocol for overcoming substrate limitations, reveals excess brain mitochondrial Complex I capacity","authors":"Naibo Zhang ,&nbsp;Brian A. Roelofs ,&nbsp;Evan A. Bordt ,&nbsp;Boris Piskoun ,&nbsp;Courtney L. Robertson ,&nbsp;Brian M. Polster","doi":"10.1016/j.freeradbiomed.2025.09.011","DOIUrl":"10.1016/j.freeradbiomed.2025.09.011","url":null,"abstract":"<div><div>Mitochondrial bioenergetic competency in cells is frequently assessed by the Mito Stress Test protocol, which includes uncoupler addition for evaluating respiratory capacity. The uncoupled oxygen consumption rate (OCR) is usually defined as maximal respiration, with little consideration of whether the measured rate is restricted by substrate supply. In this study, we show that the uncoupled OCR is substrate-limited in rat primary cortical neurons and isolated mouse forebrain synaptosomes. We use a different respirometry protocol we name CRABS-ROC (<u>C</u>omplex <u>R</u>espirometry <u>A</u>ssay <u>B</u>ypassing <u>S</u>ubstrate-<u>R</u>estricted <u>O</u>xygen <u>C</u>onsumption) that enables evaluation of individual electron transport chain (ETC) complex capacities using saturating levels of substrates to bypass this restriction. Optimization of the cytochrome <em>c</em> concentration was critical for ETC complex capacity assessment. Applying CRABS-ROC to primary cortical neurons reveals &gt;2-fold excess Complex I capacity beyond the uncoupled OCR of cells metabolizing glucose and pyruvate. Furthermore, we demonstrate that CRABS-ROC can expose a Complex I deficit in isolated harlequin mutant brain mitochondria that display wild-type levels of Complex I-substrate-linked respiration despite having about half the normal level of Complex I. Thus, CRABS-ROC should be broadly useful for studies on mitochondrial function because it can both reveal excess ETC capacity and unmask ETC alterations that may be missed by the most widely used methods.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 24-31"},"PeriodicalIF":8.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039486","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":"Neonatal liver-derived FTH1-enriched extracellular vesicles attenuate ferroptosis and ameliorate MASLD pathogenesis","authors":"Xin Zeng ,&nbsp;Wei Jiang ,&nbsp;Tian Wu ,&nbsp;Lan Li ,&nbsp;Fudong Fu ,&nbsp;Han Yao ,&nbsp;Dongbo Wu","doi":"10.1016/j.freeradbiomed.2025.09.010","DOIUrl":"10.1016/j.freeradbiomed.2025.09.010","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver pathology, lacks effective therapies. This study identifies ferroptosis—a lipid peroxidation-driven, iron-dependent form of cell death—as a central pathogenic mechanism in MASLD. Integrative proteomic and histopathological analyses of human and murine MASLD livers revealed marked ferroptosis activation, characterized by dysregulated iron metabolism (reduced FTH1 and GPX4; elevated ACSL4) and oxidative stress. To address this, neonatal liver-derived extracellular vesicles (EV<em>new</em>) enriched with FTH1, were evaluated as a therapeutic strategy. EV<em>new</em> exhibited superior biodistribution to adult-derived EVs (EV<em>adult</em>), with liver-specific tropism and proteomic enrichment of FTH1, mitochondrial proteins, and glutathione regulators. In MASLD models, EV<em>new</em> administration attenuated hepatic injury, steatosis, and fibrosis, outperforming EV<em>adult</em> by restoring iron homeostasis via FTH1-mediated suppression of lipid peroxidation. Specifically, EV<em>new</em> upregulated NRF2 and GPX4 while downregulating ACSL4 and HSP60. Neutralizing FTH1 abolished the protective effects of EV<em>new in vitro</em>, confirming that FTH1 is the key mediator. These findings establish ferroptosis as a therapeutic target in MASLD and highlight the dual capacity of EV<em>new</em> to inhibit ferroptosis. This work pioneers xenogeneic EVs-based therapy for metabolic liver diseases, offering a novel multifaceted intervention with translational potential.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 693-703"},"PeriodicalIF":8.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032988","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":"HIC2 suppresses glioblastoma progression via transcriptional repression of SEMA3A and inhibition of TGF-β signaling","authors":"Liang Zhang ,&nbsp;Jiahao Yang ,&nbsp;Xueying Ke ,&nbsp;Nan Huang ,&nbsp;Dong Zhou ,&nbsp;Haiping Cai","doi":"10.1016/j.freeradbiomed.2025.09.007","DOIUrl":"10.1016/j.freeradbiomed.2025.09.007","url":null,"abstract":"<div><div>Glioblastoma (GBM), the most aggressive primary brain tumor, is associated with dismal clinical outcomes and a critical lack of actionable therapeutic targets. Herein, we report that Hypermethylated in Cancer 2 (HIC2) is significantly downregulated in GBM tissues. <em>In vitro</em>, ectopic overexpression of HIC2 markedly suppresses GBM cell proliferation, invasion, and migration, <em>while</em> in vivo, it substantially inhibits tumor growth and prolongs survival in an orthotopic xenograft model (p &lt; 0.01). Furthermore, HIC2 induces G0/G1 cell cycle arrest and robustly promotes apoptosis. Mechanistically, HIC2 directly binds to the promoter region of Semaphorin 3A (SEMA3A), repressing its transcriptional activity. This transcriptional repression subsequently attenuates TGF-β signaling by diminishing Smad2/3 phosphorylation, a critical regulatory node of this pathway. Collectively, our findings elucidate a previously unrecognized tumor-suppressive mechanism wherein HIC2 inhibits GBM progression through modulation of the SEMA3A-TGF-β signaling axis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 674-684"},"PeriodicalIF":8.2,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145019774","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 Bre1 in mitochondrial function and energy metabolism in Drosophila models of Parkinson's disease","authors":"Zaiwa Wei ,&nbsp;Liangxian Li ,&nbsp;Xueting Fan ,&nbsp;Yafang Tang ,&nbsp;Chi Wei ,&nbsp;Yonglian Zeng","doi":"10.1016/j.freeradbiomed.2025.09.009","DOIUrl":"10.1016/j.freeradbiomed.2025.09.009","url":null,"abstract":"<div><h3>Background</h3><div>The second most common cause of autosomal recessive early-onset Parkinson's disease (PD) can be attributed to mutations in the PINK1 gene, malfunction of the mitochondria is the key pathological mechanism. Bre1 encodes an E3 ubiquitin ligase, with the discovery of Bre1's role in repairing mitochondrial damage, further investigation into its implications for PD is warranted.</div></div><div><h3>Methods</h3><div>We used the PINK1^B9 drosophila melanogaster as the PD model. The effects of Bre1 on PD phenotypes were evaluated based on the morphology of the wings and dorsal region, as well as flight ability. Immunostaining of dopaminergic neurons was used to examine neurodegeneration. Transcriptomes were used to detect the pathway directly involved. Mitochondrial structure and function were observed using electron microscopy, ATP detection, and an oxygen consumption assay. The detection of SOD activity and ROS were used to explicit the effects of Bre1 on oxidative stress. To identify the effects of Bre1 on glycolysis and tricarboxylic acid (TCA) cycle, we performed Western Blot and RT-PCR.</div></div><div><h3>Results</h3><div>We discovered that Bre1 overexpression significantly improved the phenotype of PD flies and protected their dopaminergic neurons from degeneration. More significantly, we observed that the overexpression of Bre1 markedly enhanced the respiratory capacity of mitochondrial Complex I and Complex II, elevated ATP levels, reduced ROS levels, and improved mitochondrial structural integrity. The Western Blot results demonstrate a significant increase in the critical glycolysis enzymes, Pfk and Pyk proteins. Moreover, qRT-PCR results showed a remarkably upregulation in the transcriptional level of OGDH, a critical rate-limiting enzyme in the TCA cycle. Therefore, our study suggests that Bre1 improves the phenotypes of PD model flies by attenuating mitochondrial damage and enhancing energy metabolism, offering a potential drug target for ameliorating the symptoms of PINK1 mutant autosomal recessive PD patients.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 663-673"},"PeriodicalIF":8.2,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008255","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":"Tie2 Cre mediated changes in antioxidant activity modulates blood pressure and vascular reactivity: A role for Nrf2","authors":"Neha Dhyani ,&nbsp;Michael Allen ,&nbsp;Tara L. Rudebush ,&nbsp;Lie Gao ,&nbsp;Georgette Kanmogne ,&nbsp;Biju Bhargavan ,&nbsp;Song-Young Park ,&nbsp;Irving H. Zucker","doi":"10.1016/j.freeradbiomed.2025.09.004","DOIUrl":"10.1016/j.freeradbiomed.2025.09.004","url":null,"abstract":"<div><h3>Background</h3><div>Excessive oxidative stress is well known to participate in the pathogenesis of hypertension. A major regulator of oxidative stress is the transcription factor Nuclear factor erythroid 2–related factor 2 (Nrf2). However, the role of Nrf2 in the pathogenesis of hypertension is not completely understood, especially at the endothelial cell level.</div><div>ObjectivesWe hypothesized that endothelial specific Nrf2 and its endogenous inhibitor Kelch-like ECH-associated protein 1 (Keap1) modulate vascular oxidative stress, vasomotor function and blood pressure.</div></div><div><h3>Methods</h3><div>We examined blood pressure responses to Angiotensin II (ANG II) and to L-arginine methyl ester (L-NAME) in male and female wildtype (WT), Nrf2 floxed Tie2 Cre + (Nrf2KO) and Keap1 floxed Tie2 Cre + mice (Keap1 KO). In addition, vasodilator (acetylcholine (Ach), Sodium nitroprusside (SNP) and vasoconstrictor (phenylephrine, PE) responses in isolated skeletal muscle vessels were examined. Male and female responses were analyzed separately.</div></div><div><h3>Results</h3><div>While there were no changes in baseline blood pressures between genotypes, responses to acute ANG II were enhanced in male Nrf2 KO mice and blunted in Keap1 KO mice in both males and females. Chronic ANG II increased vascular ROS, which was inhibited in vessels from Keap1 KO mice. Vascular responses to ACh and increased flow were blunted in vessels from Nrf2 KO mice and augmented in Keap1 KO mice in both male and female vessels. L-NAME blunted responses to both flow and ACh in both Nrf2 and Keap1 KO mice. Vasoconstrictor responses to PE were augmented in Nrf2 KO vessels and blunted in Keap1 KO vessels.</div></div><div><h3>Conclusions</h3><div>Tie2-mediated changes in Nrf2 is a significant modulator of vascular reactivity and a potential therapeutic target in hypertension by altering ROS and nitric oxide. Differences in chronic blood pressure modulation in males and females are likely to be due to extravascular mechanisms.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 42-52"},"PeriodicalIF":8.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008284","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":"LncRNA BASP1-AS1 drives PCBP2 K115 lactylation to suppress ferroptosis and confer oxaliplatin resistance in gastric cancer","authors":"Yupeng Zhao ,&nbsp;Wentao Liu ,&nbsp;Kaiyuan Deng ,&nbsp;Yunqin Chen ,&nbsp;Peng Zhou ,&nbsp;Congxing Liu ,&nbsp;Guangqing Jiang ,&nbsp;Junjie Wu ,&nbsp;Yihong Zhang ,&nbsp;Huiheng Qu ,&nbsp;Bingya Liu ,&nbsp;Beiqin Yu ,&nbsp;Xin Shi ,&nbsp;Jiazeng Xia","doi":"10.1016/j.freeradbiomed.2025.09.002","DOIUrl":"10.1016/j.freeradbiomed.2025.09.002","url":null,"abstract":"<div><div>In oxaliplatin-resistant gastric cancer (GC), multi-omics profiling combined with organoid libraries reveals altered metabolic pathways associated with chemoresistance. We identify a novel lactylation modification at K115 of Poly(RC)-binding protein 2 (PCBP2K115la), which confers functional oxaliplatin resistance. Mechanistic studies demonstrate that the long non-coding RNA <em>BASP1-AS1</em> assembles a complex containing Unc-51 Like Autophagy Activating Kinase 1 (ULK1) and lactate dehydrogenase A (LDHA), thereby activating LDHA enzymatic activity to increase lactate production. Elevated lactate triggers PCBP2K115la modification, disrupting PCBP2-ARIH2 interaction to inhibit ubiquitin-dependent degradation and stabilize PCBP2. Concurrently, <em>BASP1-AS1</em>-mediated histone H3K14 lactylation transcriptionally upregulates both LDHA and PCBP2, generating a self-amplifying metabolic-epigenetic circuit. This axis critically suppresses ferroptosis and maintains chemoresistance, providing actionable targets for overcoming oxaliplatin resistance in GC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 717-734"},"PeriodicalIF":8.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008247","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":"The Glucocorticoid Receptor Inhibits NRF2-Mediated Expression of SLC7A11","authors":"Sarah E. Lacher ,&nbsp;Jennifer Krznarich ,&nbsp;Daniel C. Levings ,&nbsp;Salil Saurav Pathak ,&nbsp;Miles Pufall ,&nbsp;Yi-Mei Yang ,&nbsp;Matthew Slattery","doi":"10.1016/j.freeradbiomed.2025.09.008","DOIUrl":"10.1016/j.freeradbiomed.2025.09.008","url":null,"abstract":"<div><div><em>SLC7A11</em> encodes the glutamate-cystine exchanger xCT, which is a key regulator of intracellular antioxidant capacity and extracellular glutamate levels. We have identified <em>SLC7A11</em> as a direct target of the glucocorticoid receptor (GR). The GR agonist dexamethasone represses <em>SLC7A11</em> expression in multiple cell types, from epithelial cells to astrocytes. Dexamethasone induces GR binding to multiple regulatory DNA regions at the <em>SLC7A11</em> locus, including two prominent NRF2-targeted antioxidant response element (ARE) regions. Enhancer dissection and chromatin immunoprecipitation (ChIP) assays support a tethering model in which GR directly interacts with ARE-bound NRF2 at <em>SLC7A11</em> and represses NRF2-mediated activation of this gene.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 53-63"},"PeriodicalIF":8.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008237","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":"Selenium deficiency and altered Cu/Se, Zn/Se and Cu/Zn ratios associated with GPx1 activity: non-invasive biomarkers of oxidative stress in autism spectrum disorders","authors":"Majda Dali-Sahi ,&nbsp;Meriem Benguella-Benamnsour ,&nbsp;Nawel Amraoui ,&nbsp;Yahia Harek ,&nbsp;Takwa Salmi ,&nbsp;Samira Berrahoui ,&nbsp;Cherifa Benosman ,&nbsp;Nouria Dennouni-Medjati","doi":"10.1016/j.freeradbiomed.2025.09.005","DOIUrl":"10.1016/j.freeradbiomed.2025.09.005","url":null,"abstract":"<div><div>Metal micronutrient dyshomeostasis appears to be involved in the risk of autism spectrum disorders (ASD). Selenium (Se), copper (Cu) and zinc (Zn) are essential for the defence against oxidative stress (OS), a key factor in the maintenance of synaptogenesis and neurogenesis. This study assessed plasma concentrations of Se, Cu, and Zn, along with their ratios, malondialdehyde (MDA) levels, and erythrocyte glutathione peroxidase (GPx1) activity in Algerian children with ASD.</div><div>A total of 30 subjects diagnosed with ASD and 32 neurotypically developing (ND) children participated in this study. Trace element levels were measured using a polarographic analyzer. Plasma MDA was determined by UV spectrophotometry and erythrocyte GPx1 activity using a SPECORD® 210 plus dual beam spectrophotometer (Analytik Jena German).</div><div>The Cu/Zn ratio was significantly lower in children with ASD (p &lt; 0.001), while no significant difference was found for MDA between the two study groups. However, in children with ASD, a positive correlation was found between MDA and the plasma Cu/Zn ratio (r = 0.6874, p = 0.005).</div><div>Se levels and GPx1 erythrocyte activity were significantly lower in children with ASD compared with the ND children (p &lt; 0.001; p &lt; 0.05). Cu/Se and Zn/Se ratios were significantly higher in children with ASD (p &lt; 0.001).</div><div>Sex-stratified analysis indicated a specific vulnerability to OS among boys with ASD, while no significant age-related differences were observed in children with ASD.</div><div>These findings suggest that imbalances in micronutrient ratios and a decrease in GPx1 activity favor OS, potentially contributing to ASD pathogenesis in extreme western Algeria.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 685-692"},"PeriodicalIF":8.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006054","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":"Decreasing H3K27me3 alleviates cerebral ischemia/reperfusion injury by modulating FOXP1 expression","authors":"Li He ,&nbsp;Jiawei Cao ,&nbsp;Yan Lan ,&nbsp;Yuxin Zhang ,&nbsp;Jiawen Lan ,&nbsp;Li Li ,&nbsp;Yongjuan Liu ,&nbsp;Zhongcheng Wang","doi":"10.1016/j.freeradbiomed.2025.09.006","DOIUrl":"10.1016/j.freeradbiomed.2025.09.006","url":null,"abstract":"<div><div>Elevated H3K27me3 levels during cerebral I/R injury exacerbate neuronal damage through oxidative stress, but the underlying mechanism remains to be elucidated. We hypothesized that reduced H3K27me3 confers protection by modulating FOXP1 expression. Employing multifaceted approaches, we demonstrate that H3K27me3 reduction in vivo and in vitro enhances lipid metabolism and rescues oxygen-glucose deprivation (OGD)-induced mitochondrial morphological abnormalities and functional deficits. Furthermore, chromatin immunoprecipitation sequencing analysis revealed that H3K27me3 directly targets FOXP1, a member in the negative regulation of intracellular steroid signal pathway. Further study suggested that genetic knockdown of FOXP1 abolished the protective effects of H3K27me3 reduction against I/R injury. Collectively, our findings establish H3K27me3-dependent FOXP1 repression as a central mechanism driving lipid metabolic dysregulation and mitochondrial dysfunction in cerebral I/R pathogenesis, revealing novel therapeutic targets.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 615-625"},"PeriodicalIF":8.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996822","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}