Free Radical Biology and Medicine最新文献

{"title":"ZNF831-YTHDF1-DNMT1/3a feedback loop regulates lung carcinogenesis and progression through WNT7B-FZD5-β-catenin signalling axis","authors":"Dongjiao Chen ,&nbsp;Hongqiang Chen ,&nbsp;Yong Zeng ,&nbsp;Yu Shi ,&nbsp;Fei Guo ,&nbsp;Jun Fan ,&nbsp;Zhe Zhang ,&nbsp;Shimeng Zhou ,&nbsp;Na Wang ,&nbsp;Shuangwu Deng ,&nbsp;Jinyi Liu ,&nbsp;Jia Cao ,&nbsp;Wenbin Liu","doi":"10.1016/j.freeradbiomed.2025.09.030","DOIUrl":"10.1016/j.freeradbiomed.2025.09.030","url":null,"abstract":"<div><div>Zinc finger protein 831 (ZNF831) is a typical transcription factor involved in gene expression regulation. However, its role and mechanism in lung cancer (LC) remain largely unknown. DNA methylation, hydroxymethylation, and RNA m6A modification were measured by MeDIP, hMeDIP, and MeRIP. The survival and prognostic value were identified using Kaplan-Meier and Cox regression analysis. The function effects, target molecules and signalling pathway were determined in cell and animal model. We found that ZNF831 expression was downregulated through DNA methylation during lung carcinogenesis. ZNF831 could improve survival rate and was an independent protective factor for LC patients. ZNF831 overexpression inhibited LC cell growth, invasion and migration. Conversely, ZNF831 knockdown led to opposite phenotype <em>in vitro</em> and <em>in vivo</em>. Mechanistically, ZNF831 inhibited the expression of RNA-binding protein YTHDF1 through transcriptional regulation and protein interaction. Importantly, YTHDF1 also inversely inhibited ZNF831 expression by promoting DNA methyltransferase DNMT1 and DNMT3a to induce DNA hypermethylation. In addition, ZNF831 inhibited tumor growth and progression through YTHDF1 mediated translational regulation of WNT pathway key genes WNT7B and FZD5. These results demonstrated that the feedback loop of ZNF831-YTHDF1-DNMT1/3a regulates cell growth, migration and invasion via WNT7B-FZD5-β-catenin axis, further providing a new idea for targeting epigenetic regulators of LC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 338-352"},"PeriodicalIF":8.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102651","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":"Restoration of glucose metabolic homeostasis for treating CNS diseases: mechanistic insights and potential clinical prospect","authors":"Yi-Yue Zhang ,&nbsp;Xing-Yu Long ,&nbsp;Bi-Feng Yao ,&nbsp;Jing Tian ,&nbsp;Jun Peng ,&nbsp;Xiu-Ju Luo","doi":"10.1016/j.freeradbiomed.2025.09.026","DOIUrl":"10.1016/j.freeradbiomed.2025.09.026","url":null,"abstract":"<div><div>Brain glucose metabolism orchestrates central nervous system (CNS) homeostasis via cell-type-specific metabolic networks and metabolite-mediated signaling. Recent studies have shown that dysregulated glucose metabolism can disrupt energy balance, antioxidant system stability, and neuroimmune communication, in turn exacerbating CNS diseases. Impaired neuronal oxidative phosphorylation (OXPHOS) causes energy deficits and mitochondrial dysfunction, leading to neuronal cell death. Damaged astrocyte PPP support system impairs antioxidant defenses, leading to cumulative lipid peroxidation and thus exacerbating oxidative stress. Metabolic reprogramming in microglia further links overactivation of glycolysis to neuroinflammation. Crucially, glucose-derived metabolites drive post-translational modifications (PTMs), including glycosylation, lactylation, acetylation, and succinylation, that regulate chromatin states, protein function, and pathogenic signaling pathways in CNS diseases. Therefore, therapeutic strategies targeting glucose metabolism, including targeting the glucose metabolic pathways to restore metabolic flexibility, managing the metabolism-induced PTMs, and bypassing the impaired pathways with alternative fuels, offer promising opportunities for treating CNS disorders. However, the compensatory mechanisms inherent to interconnected metabolic networks undermines single-target therapies, necessitating combination strategies to simultaneously address multiple nodes. This review provides an overview of recent advances in understanding the cell-specific glucose metabolism, glucose metabolite-driven PTMs, and their pathogenic significance in CNS diseases. We further discuss the regulators involved in different strategies to restore glucose metabolic homeostasis. Future work should integrate novel tools such as single-cell spatial metabolomics and AI-driven modelling to develop combination therapies targeting brain's constantly adjusting metabolic system, ultimately translating these discoveries into clinical treatments for metabolic dysregulation.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 411-437"},"PeriodicalIF":8.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102845","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":"Lipid peroxidation-induced cell death in Rett syndrome","authors":"Anna Guiotto ,&nbsp;Andrea Vallese ,&nbsp;Valeria Cordone ,&nbsp;Franco Cervellati ,&nbsp;Mascia Benedusi ,&nbsp;Joussef Hayek ,&nbsp;Alessandra Pecorelli ,&nbsp;Giuseppe Valacchi","doi":"10.1016/j.freeradbiomed.2025.09.033","DOIUrl":"10.1016/j.freeradbiomed.2025.09.033","url":null,"abstract":"<div><div>Rett Syndrome (RTT) is a rare neurodevelopmental disorder, primarily affecting girls (1:10,000 live births), largely caused by mutations in the X-linked gene <em>MECP2</em>, an epigenetic regulator encoding for the methyl-CpG binding protein 2 (MeCP2). Recent evidence links ferroptosis, an iron-dependent cell death characterized by lipid peroxide accumulation, to neurodegenerative and neurodevelopmental disorders like autism.</div><div>Several RTT hallmarks, including redox imbalance, excess labile iron, increased lipid peroxidation, and impaired antioxidant enzyme activity, align with ferroptosis characteristics. Therefore, we investigated ferroptosis's role in RTT using human primary fibroblasts from healthy and RTT subjects, treating them with ferroptosis inducers: erastin and RSL3.</div><div>Our findings show RTT cells are highly susceptible to ferroptosis, marked by elevated lipid peroxidation and mitochondrial reactive oxygen species (mtROS) production, crucial for ferroptotic cell death. We also observed altered iron metabolism and dysregulated ferritinophagy. RTT fibroblasts exhibited an imbalanced antioxidant defense, particularly after ferroptotic stimuli, and ferroptosis inducers worsened redox imbalance compared to controls. Importantly, a ferroptosis inhibitor (Ferrostatin-1) and a SOD mimetic (mito-TEMPO) prevented these effects and normalized the altered basal conditions of RTT cells.</div><div>In conclusion, our results reveal a general dysregulation in RTT cells contributing to increased ferroptosis sensitivity. This suggests a significant role for ferroptosis in RTT pathophysiology and progression, potentially opening new therapeutic avenues for this condition.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 243-257"},"PeriodicalIF":8.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102836","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":"\"Taxifolin modulates diabetic neuropathy and inhibits insulin fibrillation: A dual mechanistic insight\"","authors":"Nazia Imam,&nbsp;Murtaza Hussain,&nbsp;Md Nadir Hassan,&nbsp;Tariq Aziz,&nbsp;Nida Naseem,&nbsp;Md Fahim Ahmad,&nbsp;Waseem Ahmad Siddiqui,&nbsp;Rizwan Hasan Khan","doi":"10.1016/j.freeradbiomed.2025.09.015","DOIUrl":"10.1016/j.freeradbiomed.2025.09.015","url":null,"abstract":"<div><div>Diabetic neuropathy (DN), a pathological condition impacting peripheral nerves, is caused by the demyelination of nerve fibers due to damage to the protective myelin sheath. Leveraging the known therapeutic potential of phytochemicals from medicinal plants, particularly in neurodegenerative disorders, this research aimed to evaluate taxifolin's role as an anti-amyloidogenic agent on human insulin amyloid formation and its efficacy in alleviating diabetic peripheral neuropathy (DPN) in male Wistar rats. The anti-fibrillatory effect of taxifolin, even at very low concentrations, on human insulin fibrillation was comprehensively demonstrated using various biophysical techniques, including light scattering assay, Thioflavin T assay, far-UV Circular Dichroism spectroscopy, and Transmission Electron Microscopy. Additionally, taxifolin was shown to destabilize preformed human insulin fibrils in a concentration-dependent manner. In the <em>in-vivo</em> component, taxifolin-treated rats exhibited a significant divergence in behavioral parameters associated with neuropathy, such as hyperalgesia and allodynia, when compared to streptozotocin-diabetic controls. Recognizing the involvement of oxidative stress in neuronal cell damage, taxifolin was found to reduce the generation of reactive oxygen species (ROS) and suppress pro-inflammatory cytokines, specifically tumor necrosis factor-alpha (TNF-α) and nerve growth factor (NGF). Furthermore, structural alterations were observed in rat brains and sciatic nerves through histopathological and transmission electron microscopic (TEM) analyses, underscoring taxifolin's multifaceted neuroprotective effects.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 183-203"},"PeriodicalIF":8.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091703","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":"HSPH1 is essential for acrylamide-induced apoptosis and autophagy of mouse spermatogonial stem cells","authors":"Bingchun Ma ,&nbsp;Meiwei Chen ,&nbsp;Linlin Xu ,&nbsp;Chaoju Hao ,&nbsp;Jiaxiang Chen","doi":"10.1016/j.freeradbiomed.2025.09.032","DOIUrl":"10.1016/j.freeradbiomed.2025.09.032","url":null,"abstract":"<div><div>Acrylamide (ACR) is an organic compound widely used in daily life, and has been reported to cause damage to male reproductive system, while its role and mechanism in affecting the function of spermatogonial stem cells remains unknown. In this study, we showed that ACR induced apoptosis and autophagy of spermatogonial stem cell line (C18-4 cells), which was accompanied with upregulation of HSPH1. HSPH1 was subsequently shown to be involved in ACR-induced apoptosis and autophagy of C18-4 cells. In addition, Transcription factor Sp2 was identified to promote transcription of <em>Hsph1</em> gene through binding to its gene promoter. Finally, Sp2/HSPH1 signaling pathway was proved to be involved in ACR-induced apoptosis and autophagy of C18-4 cells via inducing oxidative stress, and inhibition of autophagy significantly alleviated ACR-induced apoptosis. Taken together, our results demonstrate that ACR-triggered oxidative stress induces apoptosis and autophagy of mouse spermatogonial stem cells via activating Sp2/HSPH1 signaling pathway, and autophagy plays a cytotoxic role in ACR-induced apoptosis of the cells.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 171-182"},"PeriodicalIF":8.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091622","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":"Development of novel analogs of the TRi-1 and TRi-2 selenoprotein thioredoxin reductase inhibitors with initial assessment of their cytotoxicity profiles.","authors":"Miloš Jović, Radosveta Gencheva, Karoline C Scholzen, Qing Cheng, Života Selaković, Elias S J Arnér, Igor M Opsenica","doi":"10.1016/j.freeradbiomed.2025.09.028","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.09.028","url":null,"abstract":"<p><p>The human selenoprotein thioredoxin reductases are encoded and expressed as separate cytosolic (TXNRD1) and mitochondrial (TXNRD2) isoforms, with both having been suggested as potential anticancer drug targets. The TRi-1 compound was recently shown to preferentially inhibit TXNRD1 in cells, while the TRi-2 compound seems to target both isoforms in a cellular context, albeit to different extent. Attempting to evaluate whether TXNRD1 or TXNRD2 inhibition most closely correlates with cytotoxicity we here synthesized several analogs of both TRi-1 and TRi-2, including triphenyl phosphonium derivatives designed to accumulate in mitochondria. We evaluated 11 compounds in comparison with TRi-1 and TRi-2 with regards to inhibition of TXNRD1 and TXNRD2 in pure enzyme assays, and their cytotoxicity profiles towards human lung adenocarcinoma A549 cells, with constitutively high NRF2 activity and thus potent antioxidant defense. Human squamous cell carcinoma FaDu cells with lower NRF2 and lower TXNRD1 activity were much more sensitive to the compounds. The results strengthen the notion that compound-derived inhibition of either TXNRD1 or TXNRD2 can yield cytotoxicity in human cancer cells. Comparing two pairs of matched inhibitor scaffolds for the effects of adding a triphenyl phosphonium group, we found that this moiety ensured minimal inhibition of cellular cytosolic TXNRD1 activity, as assessed using the specific RX1 activity probe, while maintaining cytotoxicity, which was thus likely involving targeting of TXNRD2 in the mitochondria. Our results represent a blueprint for initial evaluations of novel small molecule inhibitors of TXNRD1 and TXNRD2, correlating such inhibition of pure enzymes as well as in cells in relation to their cytotoxicity.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085633","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":"ATAD3A deficiency induces oxidative eustress via the complex I reverse electron transport","authors":"Jiao Meng ,&nbsp;Xiaopeng Li ,&nbsp;Mingxi Hu ,&nbsp;Xinhua Qiao ,&nbsp;Shilong Li ,&nbsp;Yuyunfei Huang ,&nbsp;Chang Chen","doi":"10.1016/j.freeradbiomed.2025.09.027","DOIUrl":"10.1016/j.freeradbiomed.2025.09.027","url":null,"abstract":"<div><div>Based on the importance of redox homeostasis, the concept of precision redox regulation has received widespread attention. As the main source of Reactive Oxygen Species (ROS) production, mitochondria play a dual role in this process: facilitating beneficial signal transmission and causing excessive oxidative damage. Numerous studies have demonstrated that this duality is not only dependent on the quantity of ROS produced but also on the different sites of production, each showing varying effects. This insight underscores the necessity and importance of accurately regulating mitochondrial redox. However, the precise regulatory system remains unclear. In our study, we discovered that specifically knocking down the <em>atad-3</em> (<em>ATAD3A</em>) gene significantly increased the level of mitochondrial ROS in nematodes and mammalian cells. We found that ATAD3A directly interacts with the complex I subunit NDUFS8, playing an integral role in complex I assembly and activity. Knocking down <em>atad-3</em> reduces complex I activity and proton leakage, increases mitochondrial membrane potential, thereby inducing reverse electron transport (RET) to produce more ROS. The induced RET-ROS may serve as a protective response to impaired mitochondrial function, activating antioxidant systems that enhance stress resistance and extend longevity in nematodes. Our findings reveal a novel function and mechanism of knocking down <em>ATAD3A</em> to precisely regulate mitochondrial ROS production. They provide evidence for the beneficial role of RET-ROS as a signal promoting longevity and underscore the importance of precision redox.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 137-149"},"PeriodicalIF":8.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080115","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":"Autophagy and mitophagy in circulating immune cells of women with polycystic ovary syndrome: A cardiovascular perspective","authors":"María Pelechá-Salvador ,&nbsp;Cecilia Fabiana Márquez-Arrico ,&nbsp;Meylin Fernández-Reyes ,&nbsp;Laura Perea-Galera ,&nbsp;Jonathan Hermenejildo ,&nbsp;Carlos Morillas ,&nbsp;Xusa Sanz-Llorens ,&nbsp;Alberto Hermo-Argibay ,&nbsp;Víctor M. Víctor ,&nbsp;Sandra López-Domènech ,&nbsp;Milagros Rocha","doi":"10.1016/j.freeradbiomed.2025.09.025","DOIUrl":"10.1016/j.freeradbiomed.2025.09.025","url":null,"abstract":"<div><h3>Introduction</h3><div>Polycystic ovary syndrome (PCOS) is a complex endocrine disorder associated with systemic inflammation, oxidative stress, and increased cardiometabolic risk. While impaired autophagy and mitophagy have been implicated in tissue-specific dysfunction, their role in circulating immune cells and relation to early vascular alterations remain unclear.</div></div><div><h3>Methods</h3><div>In this cross-sectional study, 91 women (48 controls, 43 with PCOS) underwent anthropometric and biochemical assessment. Systemic markers included myeloperoxidase (MPO), glutathione, TNFα, and sP-selectin were determined in serum. Superoxide production (dHE), mitochondrial membrane potential (TMRM), and protein levels of BECLIN1, LC3II/I, P62, NBR1, and PINK1 were assessed in peripheral blood mononuclear cells (PBMCs). Neutrophil-endothelial cell interactions were analysed as subclinical markers of endothelial dysfunction.</div></div><div><h3>Results</h3><div>PCOS patients presented hormonal, lipid, and glucose abnormalities, accompanied by redox imbalance, elevated MPO and superoxide levels, reduced glutathione, and increased mitochondrial membrane potential. Autophagy and mitophagy pathways were significantly impaired in PBMCs, and the expression of all assessed markers was reduced. These alterations were associated with androgen excess, oxidative stress, and inflammation. Elevated sP-selectin and enhanced neutrophil-endothelial interactions indicated early endothelial dysfunction in PCOS women.</div></div><div><h3>Conclusion</h3><div>Our findings reveal that women with PCOS display autophagy and mitophagy impairment in immune cells, processes that are linked to oxidative and inflammatory stress and accompanied by endothelial alterations, highlighting a potential mechanistic pathway contributing to their cardiometabolic risk.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 161-170"},"PeriodicalIF":8.2,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074732","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":"Low-dose valproic acid ameliorates osteoporosis by restoring redox homeostasis and suppressing ferritinophagy-dependent ferroptosis via EZH2/H3K27me3 signaling","authors":"Yifan Gu ,&nbsp;Ziru Wang ,&nbsp;Kun Wang ,&nbsp;Yicong Wang ,&nbsp;Yiheng Li ,&nbsp;Shuai Jiang ,&nbsp;Yu Zheng ,&nbsp;Run Feng ,&nbsp;Min Yang","doi":"10.1016/j.freeradbiomed.2025.09.023","DOIUrl":"10.1016/j.freeradbiomed.2025.09.023","url":null,"abstract":"<div><h3>Background</h3><div>Valproic acid (VPA), a histone deacetylase inhibitor, exhibits dose-dependent effects on bone homeostasis. This study investigates whether low-dose VPA protects against ovariectomy (OVX)-induced osteoporosis by targeting oxidative stress and ferroptosis.</div></div><div><h3>Methods</h3><div>OVX rats received low- (100 mg/kg/d) or high-dose (300 mg/kg/d) VPA for 12 weeks. Bone microstructure was analyzed by micro-CT. Systemic redox status was evaluated by measuring MDA, SOD, GSH, and Fe²⁺. Ferroptosis markers (GPX4, ACSL4, FTH1, NCOA4) were examined. In MC3T3-E1 cells pretreated with VPA (0.5–3 mM), erastin was used to induce ferroptosis. The EZH2/H3K27me3 pathway and osteoclastogenesis were further assessed.</div></div><div><h3>Results</h3><div>OVX induced bone loss, oxidative stress (elevated MDA/Fe²⁺, decreased SOD/GSH), and ferroptosis activation (increased ACSL4/NCOA4, decreased GPX4/FTH1). Low-dose VPA reversed these changes, improved bone density and microarchitecture, and reduced bone resorption. High-dose VPA showed no protective effects. In vitro, 1 mM VPA attenuated erastin-induced lipid peroxidation, mitochondrial damage, and ferroptosis. Mechanistically, VPA activated EZH2/H3K27me3 signaling, enhancing H3K27me3 enrichment at the NCOA4 promoter to suppress ferritinophagy and ferroptosis. VPA also inhibited RANKL-induced osteoclast differentiation.</div></div><div><h3>Conclusion</h3><div>Low-dose VPA ameliorates osteoporosis by restoring redox homeostasis, epigenetically inhibiting NCOA4-mediated ferritinophagy via EZH2/H3K27me3 activation, and suppressing osteoclastogenesis. These findings identify low-dose VPA as a multifaceted anti-osteoporotic agent and highlight the EZH2/H3K27me3/NCOA4 axis as a pivotal regulatory pathway in bone redox biology.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 76-89"},"PeriodicalIF":8.2,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063295","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":"“Susceptibility of hiPSC-derived NSCs and neurons to paraquat treatment: insights into differential neurotoxicity mechanisms related to mitochondria.”","authors":"A. Czerniczyniec ,&nbsp;S. Mucci ,&nbsp;M.A. Lopez ,&nbsp;M. Apecetche ,&nbsp;D. García-Chialva ,&nbsp;W. Quilumbaquin ,&nbsp;M. Marazita ,&nbsp;G.E. Sevlever ,&nbsp;M.E. Scassa ,&nbsp;V. Vanasco ,&nbsp;L. Romorini","doi":"10.1016/j.freeradbiomed.2025.09.024","DOIUrl":"10.1016/j.freeradbiomed.2025.09.024","url":null,"abstract":"<div><div>Environmental exposure to paraquat (PQ), a widely used herbicide, has been associated with an increased risk of neurodegenerative diseases such as Parkinson's disease. However, species-specific limitations of traditional animal models hinder mechanistic insights into human neurotoxicity. We used a human-relevant cellular platform based on neural stem cells (NSCs) and neurons derived from human induced pluripotent stem cells (hiPSCs) to investigate the differential mitochondrial response and cell fate following PQ exposure. Our results reveal that hiPSC-derived neurons exhibit markedly higher susceptibility to PQ-induced toxicity than their corresponding neural progenitor cells. The neuronal vulnerability is characterized by profound mitochondrial membrane depolarization, reduced mitochondrial mass, elevated reactive oxygen species, increased nitric oxide levels, decreased ATP production, and activation of mitochondrial-dependent apoptosis pathways, including caspase-9 and caspase-3 cleavage, concomitant with an increased BAX/BCL-X_L ratio. In contrast, hiPSC-derived NSCs maintain viability by upregulating glycolytic activity, evidenced by increased GLUT-1 expression and hexokinase activity, suggesting a metabolic adaptation that supports resistance to mitochondrial impairment. Notably, the antioxidant N-acetyl-L-cysteine partially restored mitochondrial membrane potential and metabolism in hiPSC-derived NSCs, but failed to protect neurons, highlighting cell-type-specific sensitivity. Alterations in mitochondrial dynamics, particularly decreased OPA-1 and MFN-2 protein expression in neurons, further support a disruption in mitochondrial structure and homeostasis. Our research highlights the translational potential of hiPSC-derived neural models as a powerful platform for unravelling the mechanisms of neurotoxicity induced by PQ and other chemicals associated with Parkinson's disease risk, as well as for uncovering unique cellular responses to oxidative mitochondrial stress. These findings offer critical insights into neuronal vulnerability during early development and provide a foundation for targeted interventions to preserve mitochondrial integrity in neurodegenerative contexts.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 90-103"},"PeriodicalIF":8.2,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069484","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}