Free Radical Biology and Medicine最新文献

{"title":"Aluminum Exposure Induces Ferroptosis in Spermatogenic Cells of Mice Through Iron Overload and Lipid Peroxidation.","authors":"Wei Guangji, Peng Huixin, Hu Hongfei, Lan Hai, Feng Yang, Luo Shihua, Huang Yanxin, Yuan Huixiong, Chen Wencheng","doi":"10.1016/j.freeradbiomed.2025.09.043","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.09.043","url":null,"abstract":"<p><p>Aluminum (Al) is a pervasive environmental contaminant with detrimental biological effects. Although Al exposure induces oxidative stress and toxicity in spermatogenic cells, leading to impaired male reproductive function, the underlying molecular mechanisms remain incompletely elucidated. In this study, we systematically evaluated the toxic effects of Al on spermatogenic cells using both in vivo and in vitro models. Transcriptomic profiling of GC-2spd cells revealed Al-induced differential gene expression related to oxidative stress response, iron homeostasis, and lipid metabolism regulation. These alterations were notably enriched in the ferroptosis and HIF-1 signaling pathways. Subsequent in vivo analyses demonstrated that Al exposure increased iron levels and oxidative stress while reducing ATP content in mouse testes, resulting in testicular damage, decreased sperm quality, and lowered serum sex hormone levels, all of which contribute to reproductive dysfunction. Further investigations confirmed that Al disrupts redox and iron homeostasis, promoting lipid peroxidation and ferroptosis in both mouse testes and GC-2spd cells. Importantly, administration of the ferroptosis inhibitor Ferrostatin-1 (Fer-1) effectively restored homeostasis, thereby alleviating Al-induced ferroptosis and spermatogenic cell toxicity. In conclusion, this study demonstrates that Al disrupts iron and redox balance, leading to iron accumulation and lipid peroxidation in spermatogenic cells, which triggers ferroptosis and ultimately causes male reproductive impairment. These findings identify ferroptosis as a novel therapeutic target for mitigating aluminum-related reproductive risks and provide a scientific basis for public health interventions in occupational and environmental settings grounded in this newly characterized cell death mechanism.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148547","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":"Targeting FDX1 with Icaritin attenuates neuronal cuproptosis by reconciling mitochondrial fission-fusion dynamics and bioenergetic homeostasis","authors":"Yifan He ,&nbsp;Tingting Yi ,&nbsp;Ying Yao ,&nbsp;Songyuan Duan ,&nbsp;Lianhang Wang ,&nbsp;Jianmei Gao ,&nbsp;Qihai Gong","doi":"10.1016/j.freeradbiomed.2025.09.044","DOIUrl":"10.1016/j.freeradbiomed.2025.09.044","url":null,"abstract":"<div><div>Copper overload triggers cuproptosis, a copper-dependent cell death pathway characterized by mitochondrial oxidative stress, dysfunction, and disrupted dynamics, posing significant threats to neuronal health. Icaritin (ICT), a bioactive flavonoid from <em>Herbal Epimedii</em>, exhibits antioxidant and neuroprotective properties, but its impact on cuproptosis remains unexplored. Thus, this study was aimed to investigate ICT's protective mechanisms against cuproptosis induced by the cupric sulfate and copper ionophore elesclomol (Cu-ES) in HT22 hippocampal neuronal cells. We found that Cu-ES effectively modeled cuproptosis, reducing viability by 50 % and inducing severe mitochondrial damage, oxidative stress, dysfunction, tricarboxylic acid cycle disruption, and dynamics imbalance. While ICT's treatment concentration-dependently mitigated these injuries. Mechanistically, computational molecular interaction analysis and trajectory simulations, and surface plasmon resonance confirmed ICT directly binds ferredoxin 1 (FDX1) with high affinity and stability, downregulating its protein expression. ICT consequently inhibited the FDX1-mediated cuproptosis pathway, reducing dihydrolipoamide S-acetyltransferase (DLAT) oligomerization, modulating cuproptosis sensitivity proteins, restoring copper homeostasis by increasing ATPase copper transporting beta (ATP7B) and decreasing solute carrier family 31 member 1 (SLC31A1), and suppressing the lipoylation pathway. Crucially, FDX1 knockdown abolished Cu-ES toxicity and potentiated ICT's protective effects against superoxide production, DLAT expression, and copper accumulation. Furthermore, ICT rescued mitochondrial dynamics by promoting fusion and inhibiting fission. Our findings demonstrate ICT is a potent inhibitor of neuronal cuproptosis, targeting FDX1 to alleviate mitochondrial oxidative stress, dysfunction, and dynamics disorder, presenting a promising therapeutic strategy.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 353-366"},"PeriodicalIF":8.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148569","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":"Unraveling the role of PGAM5 in doxorubicin-induced cardiotoxicity","authors":"Xianghui Zhang ,&nbsp;Yinuo Qin ,&nbsp;Chengqiang Jin","doi":"10.1016/j.freeradbiomed.2025.09.038","DOIUrl":"10.1016/j.freeradbiomed.2025.09.038","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 299-300"},"PeriodicalIF":8.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137004","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":"Exosomal miR-27a-5p inhibits indoxyl sulfate-induced cardiac dysfunction by targeting the USF2/FUT8 axis","authors":"Kun Xiao ,&nbsp;Jiaojiao Hao ,&nbsp;Nan Wang ,&nbsp;Nan Shen ,&nbsp;Bo Jiang ,&nbsp;Longkai Li ,&nbsp;Xu Zhang ,&nbsp;Weidong Wang ,&nbsp;Hui He ,&nbsp;Ziran Wang ,&nbsp;Huiyi Song ,&nbsp;Qingzhu Tang ,&nbsp;Biaojie Qin ,&nbsp;Xiangning Du ,&nbsp;Fan Yang ,&nbsp;Shuni Chen ,&nbsp;Xianan Guo ,&nbsp;Shuang Meng ,&nbsp;Hongli Lin","doi":"10.1016/j.freeradbiomed.2025.09.040","DOIUrl":"10.1016/j.freeradbiomed.2025.09.040","url":null,"abstract":"<div><div>Uremic cardiomyopathy (UCM) is the leading cause of hemodialysis patient mortality. Indoxyl sulfate (IS), a key uremic toxin, activates multiple signaling pathways, causing cardiac hypertrophy and apoptosis. We previously demonstrated that core fucosylation (CF), a post-translational modification, is crucial in activating these pathways. Additionally exosome-mediated cardiac microvascular endothelial cell (CMEC)-cardiomyocyte (CM) crosstalk is important for UCM progression. However, the characteristics and roles of CF modification in IS-induced CMEC-derived exosomes (IS-Exos) that cause CM injury remain unexplored. Our studies have revealed that hemodialysis patients had significantly higher serum IS and α1,6-fucosyltransferase (FUT8), which were positively correlated with the severity of cardiac injury. Using a microfluidic chip model of IS-induced cardiac injury, we visualized exosome transfer from CMECs to CMs, which caused mitochondrial impairment, hypertrophy and apoptosis in CMs, with elevated CF levels playing critical roles. To investigate this further, we performed FUT8 knockout in IS-mice treated with IS-Exos and transfected FUT8 siRNA into CMs exposed to IS-Exos. We found that the inhibition of FUT8 leads to a reduction in ARG2 expression, which consequently diminishes reactive oxygen species (ROS) and ameliorates cardiac hypertrophy and apoptosis. Mechanistically, miR-27a-5p was markedly downregulated in IS-Exos. CD44 on IS-Exos interacts with EGFR in CMs, enhancing cardiac injury. Supplementation with miR-27a-5p in vivo and in vitro specifically targets USF2, leading to a downregulation of FUT8 expression. This cascade leads to a diminished expression of ARG2, alleviation of ROS, and the reversal of cardiac hypertrophy and apoptosis. Our findings offer new insights, suggesting that targeting CF modification may represent a promising therapeutic strategy for alleviating UCM in the future.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 268-286"},"PeriodicalIF":8.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137088","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":"Brain rewired: Redox control of brain cell crosstalk via nanotubes and vesicles","authors":"Fuli Zheng ,&nbsp;Shangrong Jiang ,&nbsp;Xinpei Lin ,&nbsp;Xiangyu Chang ,&nbsp;Wei Wang ,&nbsp;Jianping Tang ,&nbsp;Yanjun Li ,&nbsp;Sining Liao ,&nbsp;An Zhu ,&nbsp;Wenya Shao ,&nbsp;Zhenkun Guo ,&nbsp;Xu Liu ,&nbsp;Huangyuan Li ,&nbsp;Michael Aschner","doi":"10.1016/j.freeradbiomed.2025.09.037","DOIUrl":"10.1016/j.freeradbiomed.2025.09.037","url":null,"abstract":"<div><div>Redox balance is critically important for maintaining normal physiological functions in the brain. Disruptions in this balance, whether through excessive reduction (reductive stress) or excessive oxidation (oxidative stress), can contribute to the onset and progression of neuropathological conditions. For decades, research has predominantly focused on the impact of redox imbalance in inducing nervous system damage at the level of single cells, subcellular organelles, and macromolecular changes. Recent evidence increasingly indicates that redox status not only affects intracellular processes but also plays a pivotal role in regulating intercellular communication. Specifically, redox imbalance has been shown to influence the formation of tunnelling nanotubes and the secretion of extracellular vesicles (EVs, such as microvesicles, exosomes), both of which are critical for the transfer of cellular signals, organelles, and biomolecules between cells. In this review, after a succinct introduction to key concepts related to redox biology, we present a comprehensive overview of intercellular communication and its interaction with redox balance in the brain, encompassing both genetic and epigenetic modifications.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 258-267"},"PeriodicalIF":8.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137027","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":"Activation of the Lp-PLA2/LPC axis triggers endothelial ferroptosis to drive diabetic kidney disease.","authors":"Yun Zhou, Lilong Wei, Lijuan Hu, Siqi Han, Ruyue Zhang, Yongtong Cao","doi":"10.1016/j.freeradbiomed.2025.09.036","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.09.036","url":null,"abstract":"<p><strong>Background: </strong>Endothelial dysfunction is a key driver of diabetic kidney disease (DKD), but the role of regulated cell death pathways remains unclear. Lipoprotein-associated phospholipase A2 (Lp-PLA2) and its pro-inflammatory product lysophosphatidylcholine (LPC) promote vascular injury; however, their ability to trigger endothelial ferroptosis in DKD is unknown.</p><p><strong>Methods: </strong>Using a longitudinal db/db mouse model of DKD, we inhibited Lp-PLA2 with Darapladib or administered exogenous LPC. Renal injury, endothelial function, and ferroptosis hallmarks (ROS, ACSL4, GPX4, NOX1) were assessed at multiple timepoints. In vitro, glomerular endothelial cells under high glucose (HG) were treated with Darapladib, LPC, or Lp-PLA2 overexpression to dissect causality..</p><p><strong>Results: </strong>The Lp-PLA2/LPC axis was progressively activated in DKD mice, correlating with albuminuria, endothelial dysfunction (reduced eNOS, NO, and VEGF; increased ICAM-1 and ADMA), and ferroptotic execution (elevated ROS, ACSL4, and NOX1; decreased GPX4). Darapladib suppressed ferroptosis and attenuated renal injury, whereas LPC exacerbated both. Mechanistically, HG induced ferroptosis in endothelia via Lp-PLA2/LPC activation, which was rescued by Darapladib but amplified by LPC or Lp-PLA2 overexpression.</p><p><strong>Conclusion: </strong>We identify the Lp-PLA2/LPC axis as a novel activator of endothelial ferroptosis in DKD. Pharmacological blockade with Darapladib protects the kidney by inhibiting this iron-dependent cell death, providing a mechanistically grounded therapeutic strategy independent of glycemic control.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124243","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":"Rational design of MAO-B-activated fluorescent probe for activity evaluation and its biomedical applications","authors":"Fei Yan ,&nbsp;Junxiang Niu ,&nbsp;Yue Zhang ,&nbsp;Yan Sun ,&nbsp;Jiayue Wang ,&nbsp;Guobiao Liang ,&nbsp;Jingnan Cui ,&nbsp;Yusong Ge ,&nbsp;Fangyu Yang ,&nbsp;Lei Feng","doi":"10.1016/j.freeradbiomed.2025.09.034","DOIUrl":"10.1016/j.freeradbiomed.2025.09.034","url":null,"abstract":"<div><div>Monoamine oxidase mainly includes two isoforms, monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), of which MAO-B is a crucial metabolic enzyme, acts on dopamine and <em>β</em>-phenylethylamine and can be selectively inhibited by pargyline. MAO-B has emerged as a significant drug target for a variety of nervous system diseases. In the present work, a highly selective and sensitive fluorescent probe named 3-aminopropyl (3-oxo-3<em>H</em>-phenoxazin-7-yl) carbamate (<strong>AHPC</strong>) was designed and developed. <strong>AHPC</strong> showed good stability and cell membrane permeability in biological systems, and could detect endogenous MAO-B activity in real time, and accurately evaluate the changes of MAO-B under H₂O₂-induced oxidative stress. In addition, <strong>AHPC</strong> was able to detect the distribution of MAO-B in different organs. As MAO-B is an important drug target, we developed a high-throughput, visual screening system for MAO-B inhibitors based on <strong>AHPC</strong>. <em>Glycyrrhizae radix et rhizome</em> was screened from 272 kinds of Chinese medicine and displayed strong inhibitory effect toward MAO-B. After further separation of <em>Glycyrrhizae radix et rhizome</em>, it was found that Licoisoflavone B was the main active ingredient to inhibit MAO-B activity in different enzyme sources, and was expected to be a lead compound for the treatment of MAO-B-related diseases. In conclusion, with the advantages of fluorescent probe technology, we not only developed a handy molecular tool for real-time detection of MAO-B distribution and function in complex biosystems, but also established a high-throughput visualization method for screening MAO-B inhibitors from traditional Chinese medicine, which are promising for the treatment of many MAO-B-related diseases.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 236-242"},"PeriodicalIF":8.2,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119904","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":"Accumulation of succinate in the blood is a potential early indicator of metabolic dysfunction-associated steatotic liver disease (MASLD)","authors":"Olivia Chalifoux ,&nbsp;Chloe Dagostino ,&nbsp;Meijing Li ,&nbsp;Stephanie Trezza ,&nbsp;Cathryn Grayson ,&nbsp;Mariana De Sa Tavares Russo ,&nbsp;Daina Zofija Avizonis ,&nbsp;Marek Michalak ,&nbsp;Luis B. Agellon ,&nbsp;Ryan J. Mailloux","doi":"10.1016/j.freeradbiomed.2025.09.029","DOIUrl":"10.1016/j.freeradbiomed.2025.09.029","url":null,"abstract":"<div><div>There is currently a need to identify new biomarkers to diagnose metabolic dysfunction-associated steatotic liver disease (MASLD). Here, using C57BL6N male mice fed a high-fat diet (HFD), we provide evidence that extracellular succinate buildup is a sex-dependent diagnostic marker for MASLD. Male mice fed the HFD for 2-weeks developed simple steatosis, which was associated with the plasma buildup of succinate to 50 μM. Feeding the mice this diet for up to 7 weeks advanced the condition to MASLD, resulted in cardiac fibrosis, and the further increased plasma succinate to 100 μM. Using Huh-7 hepatoma cells as a model, we found fructose overload increased the concentration of succinate in the culture media, and this was associated with mitochondrial dysfunction and the hyper production of mitochondrial hydrogen peroxide (mtH₂O₂). HepG2 hepatocellular blastoma cells subjected to fructose overload in culture also accumulated succinate in the media. Treatment of the Huh-7 and HepG2 cells exposed to fructose with ursodeoxycholic acid (UDCA) or its taurine-conjugated form, TUDCA, which are known to elicit protective hepatocellular effects by inducing antioxidant defenses, strongly inhibited succinate build up by preserving mitochondrial function and preventing H₂O₂ hyper-production. Finally, using our <em>glutaredoxin-2</em> (<em>Glrx2</em>^{<em>−/−</em>}) gene knockout mouse model on a C57BL6N background, we found deleting the <em>Glrx2</em> gene in male mice completely abrogated the accumulation of succinate, cis-aconitate, and itaconate in plasma. Importantly, wild-type (<em>Wt</em>) or <em>Glrx2</em>^{<em>−/−</em>}female littermates did not accumulate any of these metabolites in plasma when fed the HFD, which coincided with MASLD resistance. Collectively, our findings show succinate accumulates rapidly in the extracellular milieu in our mouse model for MASLD and cell culture models for hepatic lipotoxicity. These findings suggest the applicability of succinate as a biomarker of early MASLD particularly among males and especially in pediatric populations.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 220-235"},"PeriodicalIF":8.2,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119903","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":"ENO1 blockade augment ferroptosis susceptibility in TKIs-resistant CML through GPX4 autophagic degradation.","authors":"Peng Hongwei, Yang Xintong, Chen Zhiwei, Hu Jinfang, Xiong Dongsheng, Wan Jiaqi, Liu Zhen, Li Yue, Wang Xu, Ren Simei, Li Fei","doi":"10.1016/j.freeradbiomed.2025.08.055","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.08.055","url":null,"abstract":"<p><p>The introduction of tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of chronic myeloid leukemia (CML), however, approximately 20% CML patients developed resistance to TKIs and lead to treatment failure. Enolase 1 (ENO1) is a critical enzyme involved in glycolysis and was found to be closely related to CML carcinogenesis. Our results indicate ENO1 expression was close correlated with drug responses and disease prognosis in CML. The chemo-resistant CML cell K562/G more relied on glycolysis for energy supply than its sensitive counterparts.,Metabolomic analysis revealed that ENOblock, APIII-α4(AP), synergized with multiple TKIs and induce ferroptosis in K562/G cells. Bioinformatics analysis suggested that GPX4 play more crucial role in sustaining chemo-resistant CML cell survival. Transcriptomic analysis and WB results revealed GPX4 autophagic degradation induced by ENO1 downregulation. AMPK/mTOR signaling pathway activated by ENO1 downregulationplayed partial role in GPX4 degradation. More importantly, the expression of ENO1 was found to be inversely correlated with that of a transmembrane protein TMEM164.TMEM164 interference would restore the GPX4 autophagic degradation and ferroptosis susceptibility induced by ENO1 downregulation.Single-cell sequence data revealed a co-expression relationship between ENO1 and GPX4, especially in CML patients with poor TKIs responses. Besides, In vivo animal experiments demonstrated that AP could cooperate with TKIs to relieve the tumor burden with tolerable safety. Taken together, this study demonstrated that ENO1 is a crucial biomarker for CML TKIs responses, and ENO1 blockade could augment TKIs sensitivity and promote the ferroptosis susceptibility in TKIs-resistant cells by ultimately inducing GPX4 autophagic degradation through AMPK/mTOR pathway and ENO1-TMEM164 interaction, which provide a potential novel target for the clinical treatment of CML.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111945","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":"ICAT drives lactylation of tumor-associated macrophages via the c-Myc-ENO1 axis to promote cervical cancer progression","authors":"Tingting Dang ,&nbsp;Yiqing You ,&nbsp;Lan Wei ,&nbsp;Qian Li ,&nbsp;Haoli Sun ,&nbsp;MengXin Sun ,&nbsp;Xiaolu Li ,&nbsp;Shiyu Yang ,&nbsp;Tao Zeng ,&nbsp;Liang Zhang ,&nbsp;Xiran He ,&nbsp;Ke Wang ,&nbsp;Jiafeng Tang ,&nbsp;Yan Zhang","doi":"10.1016/j.freeradbiomed.2025.09.031","DOIUrl":"10.1016/j.freeradbiomed.2025.09.031","url":null,"abstract":"<div><div>The effectiveness of immunotherapy in cervical cancer (CC) is profoundly influenced by the tumor microenvironment (TME), where a high infiltration of M2-type tumor-associated macrophages (TAMs) correlates with poor therapeutic responses. Therefore, understanding the molecular mechanisms driving M2-type TAM polarization and identifying novel therapeutic targets are essential for enhancing immunotherapy outcomes in CC. In this study, ICAT was revealed to be significantly upregulated in CC, correlating with poor prognosis. Mechanistically, ICAT facilitated the nuclear translocation of c-Myc, enhancing ENO1 transcription, thereby promoting glycolytic activity and lactate accumulation in the TME. Tumor-derived lactate induced H3K18 lactylation in TAMs, which in turn activated ARG1 expression, driving M2 polarization and establishing an immunosuppressive microenvironment that supports immune evasion. In summary, this study demonstrates that ICAT, by regulating the c-Myc-ENO1 axis, mediates the interaction between tumor cells and macrophages, thereby reshaping the TME and promoting the migration, invasion, and glycolysis of CC. These findings demonstrate that ICAT represents a potential therapeutic target for the treatment of CC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"241 ","pages":"Pages 316-329"},"PeriodicalIF":8.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111972","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}