Free Radical Biology and Medicine最新文献

{"title":"Expression of Concern to \"CHIP-dependent p53 regulation occurs specifically during cellular senescence\" [Free Radical Biology & Medicine 50 (2011) 157-165].","authors":"","doi":"10.1016/j.freeradbiomed.2026.10.037","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.10.037","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223456","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 PRDX1-G6PD Interaction Promotes a Metabolic Vulnerability and Redox Imbalance in Triple-Negative Breast Cancer.","authors":"Hongru Tao, Ningyun Liu, Ziang Hu, Yixuan Xu, Heng Xu, Yuanyuan Zhang, Cheng Luo","doi":"10.1016/j.freeradbiomed.2026.10.020","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.10.020","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited targeted options, and its progression is strongly driven by metabolic reprogramming and redox homeostasis. Here, we found that peroxiredoxin-1 (PRDX1) promotes TNBC progression by directly interacting with glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP). Mechanistically, PRDX1 depletion reduced the formation of active G6PD dimers without affecting its expression, thereby impairing PPP metabolism and ultimately suppressing TNBC growth. Furthermore, we identified the natural product Oridonin as a small-molecule disruptor that blocked the PRDX1-G6PD interaction. Pharmacological intervention with Oridonin impaired G6PD dimerization, disrupted intracellular redox homeostasis and suppressed TNBC tumor growth in vivo. Taken together, our study unveils the critical role of the PRDX1-G6PD protein complex in PPP-dependent metabolic reprogramming and redox homeostasis in TNBC, and identifies this axis as a targetable vulnerability against TNBC.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220109","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":"MLKL Orchestrates ER-Mitochondria Stress to Drive Dendritic Cell Pyroptosis and Immunoparalysis in Sepsis.","authors":"Yimeng Wang, Bing Sun, Huayong Chen, Jiewei Luo, Yingping Cao","doi":"10.1016/j.freeradbiomed.2026.10.021","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.10.021","url":null,"abstract":"<p><strong>Introduction: </strong>Sepsis induces systemic inflammation and immune dysregulation, leading to immunoparalysis characterized by dendritic cells (DCs) depletion and dysfunction. Mixed lineage kinase domain-like pseudokinase (MLKL) is an oranelle stress regulator; however, its role in DCs-mediated immune regulation during sepsis remains poorly defined.</p><p><strong>Objectives: </strong>This study aimed to elucidate the role of MLKL in sepsis-associated DCs dysfunction and to determine the underlying molecular mechanisms linking MLKL to immune dysregulation and disease severity.</p><p><strong>Methods: </strong>Cecal ligation and puncture (CLP) was used to establish sepsis in wild-type (WT) and MLKL-deficient (MLKL^-/-) mice. Primary CD11c⁺ DCs and DC2.4 cells were stimulated with lipopolysaccharide (LPS), with or without MLKL knockdown. Cell death pathways, organelle stress responses, ER-phagy, and immune function were analyzed using molecular, cellular, and in vivo approaches.</p><p><strong>Results: </strong>Sepsis and LPS stimulation induced time-dependent MLKL activation and necroptosis-related signaling. MLKL deficiency attenuated NLRP3-gasdermin D-mediated pyroptosis, alleviated endoplasmic reticulum and mitochondrial stress, restored ER-phagy, and reduced reactive oxygen species production. These effects preserved DCs maturation and costimulatory molecule expression, thereby enhancing CD4⁺ T-cell activation. Mechanistically, MLKL localized to mitochondria-associated membranes and interacted with mitofusin 2 (MFN2), promoting its degradation; a specific MLKL fragment was sufficient to destabilize MFN2. In vivo, MLKL ablation reshaped inflammatory cytokine profiles, reduced multi-organ injury, and improved survival following sepsis.</p><p><strong>Conclusion: </strong>MLKL drives DCs dysfunction and immune dysregulation in sepsis by destabilizing MFN2 and impairing ER-phagy. Targeting the MLKL-MFN2-ER-phagy axis represents a potential therapeutic strategy for restoring immune competence in sepsis.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215448","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":"Transient but not sustained p53 activation by targeting METTL3 prevents radiation-induced intestinal injury through dual-regulation of revival stem cells.","authors":"Ruiqiu Zhu, Mingyue Li, Chengzhi Liu, Defu Kong, Jialu Qian, Ming Li, Ye Tian, Liwei Xie, Shang Cai","doi":"10.1016/j.freeradbiomed.2026.10.035","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.10.035","url":null,"abstract":"<p><p>Radiation-induced intestinal injury (RIII) remains a severe complication of radiotherapy. Although p53 activation is known to be protective, no clinically available p53 activators exist. Different p53 activation dynamics (transient or sustained) are linked with radio-sensitivity, yet their therapeutic relevance to RIII has not been explored. The emerging role of N6-methyladenosine (m6A) in radiation injury is recognized, but the mechanistic link between m6A and p53 signaling in RIII remains elusive. Here, we investigated how m6A regulates p53 signaling, as well as the functional consequences and mechanisms of transient or sustained p53 activation via pharmacologically targeting m6A in RIII. After radiation, m6A writer METTL3 increases m6A on MDM2 mRNA, which is recognized by m6A reader IGF2BP3, upregulating MDM2 and suppressing intestinal p53. Then, METTL3 inhibitor S-Adenosylhomocysteine (SAH) was used to induce transient or sustained p53 activation. Functionally, a single dose of SAH suppressed MDM2 and induced transient p53 activation, thereby protecting against RIII, whereas multiple dosing induced sustained p53 activation but failed to confer a protective benefit. Mechanistically, transient p53 activation prevented RIII by stimulating YAP signaling and revival stem cells (revSCs) regeneration, a newly defined stress-induced intestinal stem cell population, whereas sustained p53 activation failed to. Importantly, SAH did not protect colorectal cancer cells from radiation. Together, these findings reveal that radiation inhibits intestinal p53 expression through the METTL3/m6A/IGF2BP3/MDM2 axis, and that transient p53 activation via METTL3 inhibition offers a promising protective strategy for RIII through YAP-mediated revSCs regeneration.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215453","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":"Bisphenol A induces hepatotoxicity via a LAMP3-dependent impairment of mitophagic processing and reduced PI3K-AKT-mTOR signaling.","authors":"Bin Lu, Yuhui Shi, Xingzhi Chen, Yongheng Huang, Jie Ding, Mingxing Xu, Yuan Feng, Nan Lin","doi":"10.1016/j.freeradbiomed.2026.10.024","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.10.024","url":null,"abstract":"<p><p>Bisphenol A (BPA) is a ubiquitous environmental toxicant, but the mechanisms underlying BPA-associated hepatic injury remain incompletely understood. This study investigated the involvement of lysosome-associated membrane protein 3 (LAMP3) in mitophagy-related alterations and downstream survival signaling. Human hepatocellular carcinoma-derived Huh7 and PLC5 cells and a mouse model of 4-week BPA exposure were used. Cell proliferation and apoptosis were assessed using CCK-8, EdU, TUNEL, and flow cytometry; mitochondrial function and morphology were evaluated using JC-1, MitoTracker, reactive oxygen species detection, and transmission electron microscopy. RNA sequencing identified BPA-responsive genes, followed by LAMP3 loss- and gain-of-function experiments and chloroquine (CQ) treatment. BPA exposure was associated with proliferative arrest, apoptosis, mitochondrial dysfunction, increased oxidative stress, accumulation of acidic vesicular organelles, an increased LC3B-II/I ratio, and p62 accumulation-a pattern consistent with impaired late-stage mitophagic processing. LAMP3 was strongly upregulated after BPA exposure. LAMP3 silencing attenuated mitochondrial and cellular injury, reduced p62, increased LysoTracker signal, and increased PI3K-AKT-mTOR phosphorylation; CQ attenuated these protective changes. Conversely, LAMP3 overexpression aggravated BPA-associated injury and produced marker changes consistent with impaired autophagic processing. Together, these findings support LAMP3 as a contributor to BPA-associated cellular injury in the Huh7 and PLC5 models studied and suggest an association between LAMP3-related lysosomal alterations, impaired mitophagic processing, and reduced PI3K-AKT-mTOR signaling. Because dynamic mitophagic flux was not directly measured and LAMP3 was not targeted in vivo, the proposed pathway requires confirmation using tandem flux reporters, primary human hepatocytes, and in vivo genetic models.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149192654","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":"Redox resilience in skeletal muscle aging: cellular adaptations and exercise-mediated homeostasis.","authors":"Eva Tamayo-Torres, Miriam Martinez-Canton, Silvana Soto-Rodriguez, Abril Gorgori-Gonzalez, Julian Carretero, Juan Ignacio Cervera-Miguel, Olga Laosa, Leocadio Rodriguez-Mañas, Maria Carmen Gomez-Cabrera","doi":"10.1016/j.freeradbiomed.2026.10.023","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.10.023","url":null,"abstract":"<p><p>Aging progressively impairs skeletal muscle function, leading to sarcopenia, frailty, and loss of independence. Although oxidative stress has long been considered a central driver of muscle aging, increasing evidence indicates that reactive oxygen species (ROS) also serve essential signaling functions that coordinate mitochondrial remodeling, proteostasis, metabolism, and tissue repair. Consequently, age-related muscle dysfunction is increasingly understood as reflecting impaired adaptive redox signaling rather than excessive oxidant production alone. In this review, we propose the concept of redox resilience as an integrative framework describing the capacity of skeletal muscle to preserve structural integrity and functional performance through the dynamic regulation of oxidant production, antioxidant defenses, and redox-sensitive signaling in response to physiological challenges. We discuss how aging disrupts this resilience through impaired redox-sensitive signaling, including the attenuation of exercise-induced Nrf-2 activation, together with alterations in the multicellular organization of skeletal muscle. Recent advances in single-cell and single-nucleus transcriptomics have revealed that muscle aging involves profound remodeling of specialized myonuclear populations, stromal cells, immune cells, and intercellular communication networks, highlighting the multicellular complexity of skeletal muscle aging and providing a framework to investigate how redox-dependent processes may interact with tissue-wide signaling networks. We further examine how regular physical exercise reinforces redox resilience by promoting transient ROS-mediated signaling through NADPH oxidases, activation of Nrf-2 and PGC-1α-dependent pathways, mitochondrial quality control, and metabolic remodeling. These adaptations enhance the capacity of skeletal muscle to respond to physiological stress while preserving tissue homeostasis. Finally, we discuss future perspectives for targeting adaptive redox networks to promote healthy muscle aging and propose that restoring redox resilience may preserve physiological ROS signaling while strengthening endogenous antioxidant responses and limiting excessive oxidative damage, thereby contributing to the maintenance of muscle function and health span.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149192603","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":"Sdhd hypermethylation promotes succinate accumulation and NLRP3-related pyroptosis in septic lung injury.","authors":"Yan Fan, Haiyan Zhang, Shuqi Meng, Shuang Li, Lintao Lou, Keliang Xie, Jiang Xie","doi":"10.1016/j.freeradbiomed.2026.10.022","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.10.022","url":null,"abstract":"<p><p>Sepsis-induced acute lung injury (Si-ALI) involves metabolic and inflammatory dysregulation; however, its underlying mechanisms remain unclear. Here, we investigated the role of succinate accumulation and epigenetic silencing of succinate dehydrogenase subunit D (SDHD) in Si-ALI using septic mice, macrophages, and a publicly available transcriptomic dataset from patients with sepsis. Succinate supplementation increased lung inflammation, macrophage pyroptosis, and mortality in septic mice. Analysis of the GSE54514 dataset showed reduced SDHD expression in patients with sepsis. In septic mice, Sdhd overexpression reduced succinate accumulation, pyroptosis, lung injury, and mortality. In macrophages, Sdhd overexpression reduced oxidative mitochondrial DNA (ox-mtDNA) release and NLRP3-related pyroptosis. Mechanistically, sepsis-induced upregulation of DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) was associated with Sdhd promoter hypermethylation and reduced Sdhd expression. Pharmacological DNMT inhibition with SGI-1027 reversed Sdhd promoter hypermethylation, restored Sdhd expression, reduced succinate accumulation and pyroptosis, and ameliorated lung injury. These findings support a DNMT-SDHD-succinate axis in sepsis-induced lung injury and suggest that targeting this pathway may represent a potential therapeutic target for Si-ALI.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149192617","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":"Integrated Roles of The Thioredoxin-related Protein of 14 kDa, TRP14, in Sulfur Amino Acid Metabolism, Protein Posttranslational Modifications and Signaling.","authors":"Juan Sastre, Avia J Simmons, Antonio Miranda-Vizuete, Elias S J Arnér, Peter Nagy, Antonio Martínez-Ruiz, Edward E Schmidt","doi":"10.1016/j.freeradbiomed.2026.10.033","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.10.033","url":null,"abstract":"<p><p>Thioredoxins and glutaredoxins are typically small \"redoxin\" proteins that play predominant roles in shuttling reducing power from the primary nicotinamide adenine dinucleotide phosphate (NADPH)-dependent disulfide reductases, thioredoxin reductase (TrxR, TXNRD) and glutathione disulfide-reductase (Gsr) to diverse downstream substrates. Cells can have dozens to hundreds of redoxin proteins, which in combination will reduce a vast array of substrates, including proteins, metabolites, and others. Whereas there is considerable overlap between different redoxins and their preferred substrates, the thioredoxin-related protein of 14 kDa, TRP14 (also named TXNDC17), has unique characteristics that support its critical roles in cysteine acquisition and mediation of redox-regulation in cellular signaling. TRP14 is particularly efficient at cystine reduction and at modulating protein nitrosylation, cysteinylation, and persulfidation, yet it does not effectively reduce many common redoxin substrates including redox enzymes and oxidative stress-induced protein-disulfides. We propose that this functional specialization allows TRP14 to support its essential roles in cysteine acquisition and signaling under both normal and oxidative stress conditions, in the latter case, wherein other redoxins likely become overwhelmed resolving oxidative stress. Specialized attributes of TRP14 are reviewed and discussed here.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180424","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":"Hepatic HSD17B6 promotes lipid accumulation and M1 macrophage polarization via the 9-cis-retinoic acid and RXRα axis.","authors":"Xiaona Cheng, Kaikai Lu, Zizhen Guo, Luyun Yang, Keyu Yang, Kexin Cheng, Litao Wu, Chunyan Yin, Muhammad Shahzad, Dongmin Li","doi":"10.1016/j.freeradbiomed.2026.10.029","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.10.029","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly prevalent and lacks effective therapies. Hydroxysteroid 17-beta dehydrogenase 6 (HSD17B6), a liver-enriched enzyme involved in retinoid and steroid metabolism, has not been functionally characterized in MASH pathogenesis.</p><p><strong>Methods: </strong>Transcriptomic analysis of PDCD4-deficient livers identified HSD17B6 as a key upregulated gene. Its expression was validated in human MASH liver samples and murine MASH models and localized primarily to hepatocytes via single-cell RNA sequencing. Hepatic 9-cis-retinoic acid (9cRA) was quantified by HPLC. Functional consequences of HSD17B6 modulation were assessed in stable gain- and loss-of-function hepatocyte models. Underlying mechanisms were dissected using siRNA silencing and pharmacological inhibitors.</p><p><strong>Results: </strong>PDCD4 deficiency upregulated HSD17B6, leading to increased hepatic 9cRA. 9cRA activated the nuclear receptor RXRα, which in turn promoted lipid accumulation by transactivating genes such as SCD1 and CD36. Concurrently, RXRα activation directly stimulated the transcription and secretion of the chemokine CXCL10 from hepatocytes, which drove M1 macrophage polarization via CXCR3. Both genetic and pharmacological inhibition of RXRα effectively mitigated HSD17B6-driven lipid dysregulation and macrophage-mediated inflammation.</p><p><strong>Conclusions: </strong>Using a PDCD4-deficient mouse model and complementary in vitro and human data, this study identifies HSD17B6 as an important contributor to hepatic lipid accumulation and inflammation in MASH. Mechanistically, HSD17B6 promotes these pathological processes through modulation of the 9cRA-RXRα signaling axis. These findings provide new insights into the metabolic-inflammatory crosstalk underlying MASH progression and suggest that the HSD17B6-RXRα pathway may represent a potential therapeutic target for mitigating hepatic steatosis and inflammation.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180339","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":"SOCS1/Wnt/IL-1β axis negatively regulates macrophage extracellular traps and M1 polarization through the TNF pathway in crystalline kidney injury.","authors":"Zefeng Xue, Yushi Sun, Bojun Li, Ting Rao, Yuan Ruan, Xiangjun Zhou, Fan Cheng","doi":"10.1016/j.freeradbiomed.2026.10.002","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.10.002","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Calcium oxalate (CaOx) crystals are known to induce kidney damage and trigger inflammatory responses. However, the role of macrophage extracellular traps (METs) in CaOx-induced kidney injury and the relationship between METs and the M1 polarization phenotype of macrophages remain unclear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A CaOx crystal deposition model was established in C57BL/6J mice using a high-calcium diet supplemented with vitamin D. Renal tissues from patients with CaOx stones and healthy controls were also collected. In vitro, mouse RAW264.7 macrophages (RAW cells) were stimulated with calcium oxalate monohydrate (COM) crystals or IL-1β. Immunofluorescence, flow cytometry, qRT-PCR, and western blotting were used to assess METs formation and M1 polarization. Genes regulating IL-1β expression were screened using TCMK-1 renal tubular epithelial cells. mRNA sequencing was performed in both cell types to identify relevant signaling pathways. In TCMK-1 cells and mouse kidneys, SOCS1 was overexpressed or knocked down using lentivirus or siRNA. CHIR-99021 and TNFR2-Fc were used to activate the Wnt signaling pathway and inhibit the TNF signaling pathway, respectively. In the in vivo model with regulated SOCS1 expression, METs levels and M1 polarization were quantified, and the potential feedback loop between METs and the TNF signaling pathway was examined through co-culture and sequential stimulation experiments.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We found that renal tissues from patients with calcium oxalate stones and from mice with crystal deposition exhibited marked accumulation of macrophage extracellular traps (METs), identified as citH3&lt;sup&gt;+&lt;/sup&gt;/SYTOX-Green&lt;sup&gt;+&lt;/sup&gt; extracellular structures, accompanied by significantly increased M1-polarized (iNOS&lt;sup&gt;+&lt;/sup&gt;) macrophage infiltration. Calcium oxalate monohydrate (COM) crystals directly triggered MET formation and M1 polarization in RAW264.7 macrophages, and IL-1β stimulation alone was sufficient to reproduce these effects. METs themselves further promoted M1 polarization. In TCMK-1 renal tubular epithelial cells, we identified SOCS1 as a negative regulator of IL-1β transcription acting through the Wnt signaling pathway; accordingly, SOCS1 overexpression in mice markedly reduced renal MET burden and M1 macrophage infiltration in oxalate nephropathy. Mechanistically, IL-1β activated the TNF signaling pathway, which was both necessary and sufficient for MET release and subsequent M1 polarization. In turn, METs sustained TNF pathway activity, establishing a positive feedback loop that amplified both MET formation and M1 polarization. Disruption of TNF signaling abrogated this loop and significantly attenuated M1 polarization in vitro and in vivo.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;In the renal microenvironment of CaOx crystal deposition, IL-1β induces METs formation by activating the TNF signaling pathway and promotes M1 polarization. In turn, METs sustain the ","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":8.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180459","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}