Life sciences最新文献

{"title":"HHcy promotes hypertension by activating ferroptosis via suppression of the renal H₂S-SLC7A11/GPX4 axis","authors":"Pan Huang ,&nbsp;Kexin Zhang ,&nbsp;Ying Chen ,&nbsp;Jiaxin Cheng ,&nbsp;Shuangshuang Yang ,&nbsp;Lin Shi ,&nbsp;Yajuan Wang ,&nbsp;Qin Zhang","doi":"10.1016/j.lfs.2026.124247","DOIUrl":"10.1016/j.lfs.2026.124247","url":null,"abstract":"<div><div>Elevated homocysteine (Hcy) is an independent risk factor for hypertension, and kidney is an important organ for Hcy metabolism and blood pressure regulation, and its damage is closely related to the process of hypertension. Recent evidence suggests that ferroptosis, an oxidative stress-related form of cell death, contributes significantly to hypertensive organ damage. However, whether Hcy aggravates renal injury in H-type hypertension by destroying renal hydrogen sulfide (H₂S) metabolism and driving ferroptosis is still lack of direct evidence. In this study, the H-type hypertensive rat model induced by high methionine diet combined with HK-2 cell model was studied. We observed a significant increase in blood pressure and plasma Hcy in the Hcy group, accompanied by renal dysfunction and renal tubular injury. Specifically, in the renal tissue of Hcy group rats, the levels of KIM-1, Fe²⁺ and malondialdehyde (MDA) were increased, glutathione/glutathione disulfide (GSH/GSSG) ratio decreased, SLC7A11 expression was down-regulated, and GPX4 activity was inhibited. Concurrently, H₂S levels and cystathionine-beta-synthase (CBS) activity were decreased. In vitro experiments using HK-2 cells confirmed that Hcy could down-regulate the expression of CBS, cystathionine-gamma-lyase (CSE), SLC7A11, GPX4 and GSH/GSSG ratio, and up-regulate MDA and reactive oxygen species (ROS) levels. Treatment with H₂S donor (NaHS) or ferroptosis inhibitors (Ferrostatin-1, Fer-1) could rescue these changes. Collectively, our results demonstrate that high Hcy promotes hypertension by suppressing endogenous H₂S generation, downregulating the SLC7A11/GPX4 signaling axis, and inducing ferroptosis. These findings reveal a new mechanism by which Hcy aggravates hypertension by inhibiting H₂S synthesis and inducing ferroptosis.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124247"},"PeriodicalIF":5.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise alleviates the obesity-related dysfunction of skeletal muscle and heart caused by Akh gene knockdown in Drosophila","authors":"Ying Lin ,&nbsp;Deng-tai Wen ,&nbsp;Qing-yao Sun ,&nbsp;Shou-zhi Lv ,&nbsp;Ji-ying Wang ,&nbsp;Xing-feng Ma","doi":"10.1016/j.lfs.2026.124237","DOIUrl":"10.1016/j.lfs.2026.124237","url":null,"abstract":"<div><div>The Adipokinetic hormone (Akh), a functional analog of mammalian glucagon, plays a key role in regulating energy metabolism in <em>Drosophila</em>. Although exercise is recognized as an important intervention for preventing and alleviating obesity-related complications, its efficacy against obesity induced by <em>Akh</em> gene deficiency remains unclear. In this study, the <em>Akh</em> gene was knocked down systemically and specifically in the corpora cardiaca (CC) using <em>Act-gal4/Akh-UAS-RNAi</em> and <em>Akh-gal4/Akh-UAS-RNAi</em> systems in flies, and these flies were followed by a two-week exercise intervention. The results showed <em>Akh</em> knockdown induced obesity phenotypes, including significantly increased body weight and triglyceride levels, and concurrently impaired skeletal muscle and cardiac function—manifested as reduced climbing speed, climbing endurance, and cardiac shortening fraction, along with elevated heart rate. Mechanistically, these effects were associated with upregulated systemic <em>FASN1</em>/<em>Mdy</em>/triglyceride process and lipotoxicity (MDA), as well as downregulated mitochondrial (<em>PGC-1α</em>) and contractile (<em>Mhc</em>) markers in muscle. Exercise intervention ameliorated the obesity phenotype and was correlated with increased <em>Akh</em> expression. These findings confirm that <em>Akh</em> gene deficiency contributes to hereditary obesity and obesity-related dysfunction of skeletal muscle and heart, and demonstrate that exercise can serve as a therapeutic strategy to counteract impairments resulting from <em>Akh</em> knockdown, suggesting its potential relevance for treating human obesity linked to glucagon-related genetic defects.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124237"},"PeriodicalIF":5.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of Galectin-3 in the epidermis exacerbates psoriasis pathogenesis via inhibiting autophagy","authors":"Shanshan Han ,&nbsp;Meiqi Cheng ,&nbsp;Shengtao Jiang ,&nbsp;Pei Liu ,&nbsp;Yue Hu ,&nbsp;Qiong Wang ,&nbsp;Yu Cai ,&nbsp;Yinhong Song ,&nbsp;Xuan Xia ,&nbsp;Yuxin Wang ,&nbsp;Yang Li ,&nbsp;Jin Chao ,&nbsp;Decheng Wang","doi":"10.1016/j.lfs.2026.124238","DOIUrl":"10.1016/j.lfs.2026.124238","url":null,"abstract":"<div><h3>Aims</h3><div>Galectin-3 (Gal3) is linked to psoriasis pathophysiology, however, the detailed mechanism of Gal3 involved in this course still needs further addressing. This study aimed to elucidate the role of Gal3 in psoriasis.</div></div><div><h3>Materials and methods</h3><div>Imiquimod (IMQ)-induced psoriasis model in wild-type (WT) as well as Gal3 knockout (<em>Gal3</em>^−/−) mice were established to investigate the impact of Gal3 expression on the development of psoriasis. Autophagy markers LC3 and P62 (SQSTM1) were detected. In vitro, HaCaT cells with Gal3 knockdown were established to detect the effect on the autophagic flux. Then the Sirt1 agonist SRT1720 was used to demonstrate whether Gal3 affects autophagy via Sirt1. The regulation of Sirt1 by Gal3 was demonstrated through half-life experiments.</div></div><div><h3>Key findings</h3><div>Gal3 was significantly reduced in the epidermis in IMQ-induced psoriasis model. The skin inflammation in <em>Gal3</em>^−/− mice more severe than that in WT controls. A deficiency of Gal3 not only reduced the autophagy in psoriatic lesions of the mice model but also effectively inhibited autophagy in a cultured HaCaT cell model. Gal3 was demonstrated to be involved in the assembly of autophagosomes by regulating autophagic flux. In Gal3-depleted mouse skin and HaCaT cells, Sirt1 was downregulated, and SRT1720 could compensate for the impaired autophagy caused by Gal3 deficiency. Gal3 may be involved in the regulation of Sirt1 protein stability.</div></div><div><h3>Significance</h3><div>Gal3 loss exacerbates psoriasis by impairing the autophagic process. These findings position Gal3 as a key protective factor against psoriasis, providing new insights into its role in the pathogenesis of this disease.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124238"},"PeriodicalIF":5.1,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-intensity interval training attenuates the progression of diastolic and skeletal muscle dysfunction in the two-hit mouse model of HFpEF","authors":"Francisco Pino-De la Fuente ,&nbsp;Mayarling F. Troncoso ,&nbsp;Sebastián Urquiza-Zurich ,&nbsp;David Silva ,&nbsp;Magda C. Díaz-Vesga ,&nbsp;Danica Jiménez-Gallegos ,&nbsp;Rocío Bascuñan ,&nbsp;Angélica Ortega-Muñoz ,&nbsp;Raúl Vivar ,&nbsp;Claudia Muñoz-Rodriguez ,&nbsp;Raúl Flores-Vergara ,&nbsp;Alejandra Hernández ,&nbsp;Alejandra Guerrero-Moncayo ,&nbsp;Ximena Calle-Chalco ,&nbsp;Pablo F. Castro ,&nbsp;Luigi Gabrielli ,&nbsp;Mario Chiong ,&nbsp;Rodrigo Troncoso ,&nbsp;Luis Michea ,&nbsp;Sergio Lavandero","doi":"10.1016/j.lfs.2026.124248","DOIUrl":"10.1016/j.lfs.2026.124248","url":null,"abstract":"<div><h3>Background</h3><div>Heart failure with preserved ejection fraction (HFpEF) is a multifactorial syndrome characterized by diastolic dysfunction, metabolic disturbances, and skeletal muscle impairments. Exercise training has been recommended as non-pharmacological therapy for HFpEF. Yet its effects on cardiac, renal, skeletal muscle, and metabolic homeostasis remain incompletely understood.</div></div><div><h3>Aim</h3><div>We investigated the systemic effects of exercise training in the “two-hit” mouse model of HFpEF.</div></div><div><h3>Methods</h3><div>Male C57BL/6 N mice were assigned to either a sedentary HFpEF group (20 weeks) (<em>n</em> = 10) or a high-intensity interval training (HIIT) intervention for five weeks (training was initiated in the 15th week of the protocol) (n = 10), and a control group (<em>n</em> = 8). Cardiac function was assessed via echocardiography, while glucose metabolism, renal function, and skeletal muscle adaptations were evaluated through metabolic assays, histological analyses, and molecular studies.</div></div><div><h3>Results</h3><div>HIIT reduced diastolic dysfunction, as indicated by a slightly lower E/e′ ratio and reduced myocardial collagen deposition. Skeletal muscle integrity was improved, with a higher proportion of oxidative fibers in the gastrocnemius, while the quadriceps showed hypertrophy in both oxidative and less oxidative fibers. It also promotes an anabolic environment and mitochondrial enhancement. Force generation was also increased. Furthermore, HIIT reduced insulin levels without affecting renal function but decreased markers of kidney damage.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that HIIT attenuates diastolic and skeletal muscle dysfunction in the two-hit HFpEF mice model. Understanding how exercise training influences HFpEF phenotypes could provide novel insights into therapeutic strategies for patients with cardiovascular and metabolic comorbidities.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124248"},"PeriodicalIF":5.1,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced antiproliferative and anti-inflammatory effects of combined metformin, tadalafil, and tamsulosin in a rat model of testosterone-induced benign prostatic hyperplasia","authors":"Samar S. Khalaf ,&nbsp;Aya M. Sherif ,&nbsp;Eman T. Mehanna ,&nbsp;Ranwa A. Elrayess ,&nbsp;Noha M. Mesbah ,&nbsp;Dina M. Abo-Elmatty ,&nbsp;Mohamed M. Hafez","doi":"10.1016/j.lfs.2026.124240","DOIUrl":"10.1016/j.lfs.2026.124240","url":null,"abstract":"<div><h3>Aims</h3><div>Benign prostatic hyperplasia (BPH) is a common condition in aging men, associated with hormonal imbalances, oxidative stress, and inflammation. This study evaluated the effects of metformin, tadalafil, and tamsulosin administered individually or in combination on testosterone-induced BPH.</div></div><div><h3>Materials and methods</h3><div>Following BPH induction, 48 male Wistar rats were divided into six groups: normal control, BPH control, and four treatment groups receiving metformin (500 mg/kg/day), tadalafil (2 mg/kg/day), tamsulosin (10 μg/kg/day), or their combination for two weeks. Serum levels of urea, creatinine, uric acid, reduced glutathione (GSH), and malondialdehyde (MDA) were measured using enzymatic colorimetric assays. Prostate tissue levels of prostate-specific antigen (PSA), estradiol, dihydrotestosterone (DHT), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and tumor necrosis factor-alpha (TNF-α) were analyzed via ELISA. mRNA expression of cyclooxygenase-2 (COX-2), transforming growth factor β-2 (TGFβ-2), insulin growth factor-2 (IGF-2), and bone morphogenetic protein 5 (BMP5) was assessed by quantitative real-time PCR.</div></div><div><h3>Key findings</h3><div>Histopathological examination confirmed BPH induction through increased prostate weight and prostate index. While monotherapies alleviated BPH-related changes, com-bination therapy showed superior antioxidant activity and significantly improved kidney function markers. It also markedly reduced PSA, estradiol, and DHT levels, along with significant downregulation of COX-2, TGFβ-2, IGF-2, BMP5, NF-κB, and TNF-α.</div></div><div><h3>Significance</h3><div>although individual treatments provided benefits, their combined use enhanced therapeutic outcomes through modulation of oxidative stress, inflammation, and androgenic activity in BPH management.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124240"},"PeriodicalIF":5.1,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STAT1/SLC31A1 signaling promotes diabetic retinopathy progression by mediating cuproptosis-induced M1 polarization in microglial cells","authors":"Jiayang Huang ,&nbsp;Qiang Hu ,&nbsp;Xue Zhang ,&nbsp;Hongsong Peng ,&nbsp;Shan Luo ,&nbsp;Zhangxin Huang ,&nbsp;Jitian Guan ,&nbsp;Ali Hafezi-Moghadam ,&nbsp;Bo Jiang ,&nbsp;Dawei Sun","doi":"10.1016/j.lfs.2026.124241","DOIUrl":"10.1016/j.lfs.2026.124241","url":null,"abstract":"<div><div>One of the main causes of vision impairment in diabetics is diabetic retinopathy (DR). However, the molecular mechanisms controlling its progression remains incompletely known. In this research, we identified the STAT1/SLC31A1 signaling pathway as a key regulator of cuproptosis-induced M1 polarization in microglial cells, thereby contributing to the pathogenesis of DR. STAT1 expression was markedly elevated under settings of high glucose (HG), both in in vitro experiments and in streptozotocin (STZ)-induced diabetic mouse models. Mechanistically, STAT1 transcriptionally upregulated the copper transporter SLC31A1, leading to copper accumulation and enhanced cuproptosis, as indicated by decreased levels of L-DLAT, FDX1, and NDUFS8. This cellular stress promoted M1 polarization and increased the expression of pro-inflammatory cytokines. Inhibition of either STAT1 or SLC31A1 significantly attenuated HG-induced cuproptosis and microglial activation. In vivo, STAT1 inhibition reduced retinal inflammation and structural damage, supporting its pathological role in DR progression. These findings confirm that the STAT1/SLC31A1/cuproptosis axis is a critical driver of microglial polarization and retinal injury and imply that SLC31A1 may act as DR's potential therapeutic target.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124241"},"PeriodicalIF":5.1,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A protective role of ECSIT in chemotherapy-induced intestinal mucositis by maintaining Lgr5+ intestinal stem cells and gut homeostasis","authors":"Shuai Wang ,&nbsp;Yuying Jiang ,&nbsp;Jie Yu ,&nbsp;Pingping Cao ,&nbsp;Yan Chen ,&nbsp;Tianqi Shen ,&nbsp;Jukun Zhang ,&nbsp;Shuo Yang ,&nbsp;Ping Wang ,&nbsp;Fan Lin ,&nbsp;Yingjian Zhang","doi":"10.1016/j.lfs.2026.124236","DOIUrl":"10.1016/j.lfs.2026.124236","url":null,"abstract":"<div><h3>Aims</h3><div>Chemotherapy-induced intestinal mucositis (CIM) is a common and severe side effect linked to disrupted intestinal stem cell (ISC) balance, though its molecular regulation remains unclear. The principal objective of this research was to elucidate the role of evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) in intestinal stem cell balance and mucosal repair during CIM, with a specific focus on the Wnt/β-catenin pathway.</div></div><div><h3>Materials and methods</h3><div>This study used multi-omics and gene editing to elucidate ECSIT's role in intestinal stem cell balance and mucosal repair via the Wnt/β-catenin pathway. Multi-omics and Gene Set Enrichment Analyses (GSEA) identified ECSIT as a key CIM regulator.</div></div><div><h3>Key findings</h3><div>Chemotherapeutic drugs dose-dependently reduced ECSIT expression in intestinal epithelial cells. Clinical analysis revealed that ECSIT expression decreased with increasing pathological severity (normal &gt; inflammation &gt; adenocarcinoma). In intestinal epithelium-specific knockout mice, ECSIT deficiency worsened irinotecan (CPT11)-induced CIM and blocked β-catenin nuclear translocation. ECSIT stabilized the β-catenin complex, regulating Wnt target genes like Axis inhibition protein (<em>AXIN</em>) and Cyclin D1 (<em>CCND1</em>); its knockout reduced Wnt signaling. Single-cell sequencing (scRNA-seq) revealed that ECSIT knockout reduced Lgr5 stem cells and increased inflammatory cell infiltration. Lgr5-specific inducible knockout and ECSIT complementation demonstrated that restoring ECSIT reversed β-catenin inhibition and improved CIM pathology.</div></div><div><h3>Significance</h3><div>This study clarified ECSIT's dual role in stabilizing β-catenin and sustaining Wnt signaling—regulating Lgr5 intestinal stem cell proliferation and differentiation, epithelial renewal, and immune balance. These findings offer insights into CIM pathogenesis and establish the basis for developing targeted therapy through ECSIT-Wnt axis regulation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124236"},"PeriodicalIF":5.1,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Light exposure-induced circadian rhythm disruption impairs male reproductive health through oxidative stress and apoptosis","authors":"Guodong Liu ,&nbsp;Yuyang Zhang ,&nbsp;Hui Gao ,&nbsp;Xu Wu ,&nbsp;Feng Li ,&nbsp;Wei Zhang ,&nbsp;Hui Jiang ,&nbsp;Xiansheng Zhang","doi":"10.1016/j.lfs.2026.124222","DOIUrl":"10.1016/j.lfs.2026.124222","url":null,"abstract":"<div><h3>Aims</h3><div>Artificial light exposure at night and irregular light schedules are increasingly prevalent environmental stressors in modern society and have been implicated in male reproductive disorders. This study aimed to determine how distinct patterns of circadian rhythm disruption differentially affect male reproductive function and to elucidate the underlying mechanisms.</div></div><div><h3>Materials and methods</h3><div>Three groups of male rats were subjected to standard 12-h light/12-h dark cycles (LD), fixed inverted light-dark cycles (DL), and a dynamic alternating light-dark-dark-light cycle (LDDL) designed to induce circadian rhythm instability. Reproductive outcomes including body weight, testicular index, serum testosterone levels, and sperm parameters were assessed. Testicular oxidative status was evaluated by measuring NOX4/5, HO-1, SOD, and MDA levels, while apoptosis was examined using Bax/Bcl-2 ratio, cleaved caspase-3 expression, and TUNEL staining.</div></div><div><h3>Key findings</h3><div>Male rats exposed to the LDDL cycle exhibited significant reproductive dysfunction, manifested as markedly reduced testicular index, decreased serum testosterone concentration, and impaired sperm motility. Mechanistically, LDDL conditions enhanced testicular oxidative stress, manifested by NOX4/5 upregulation and HO-1/SOD suppression. This redox imbalance was accompanied by germ cell apoptosis activation, evidenced by elevated Bax/Bcl-2 ratios, increased cleaved caspase-3 expression, and a higher proportion of TUNEL-positive cells. Notably, reproductive damage was more pronounced under dynamic circadian rhythm disruption than under fixed light-dark reversal conditions.</div></div><div><h3>Significance</h3><div>By linking dynamically light-induced circadian disruption to testicular oxidative stress and apoptotic signaling pathways, it elucidates potential mechanisms by which modern lighting environments impair male fertility and provides strategies for circadian rhythm intervention and environmental mitigation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124222"},"PeriodicalIF":5.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The roles of extrachromosomal DNA in tumorigenesis and therapeutic resistance in cancer","authors":"Yidan Zhang ,&nbsp;Jiale Li ,&nbsp;Hongbin Wang ,&nbsp;Chang Xu ,&nbsp;Qiang Liu","doi":"10.1016/j.lfs.2026.124223","DOIUrl":"10.1016/j.lfs.2026.124223","url":null,"abstract":"<div><div>Extrachromosomal DNA (ecDNA) is a form of circular DNA that exists independently of chromosomes. Predominantly observed in tumor cells, ecDNA represents a key manifestation of genomic instability in cancer. In contrast to chromosomal DNA, ecDNA has a circular structure, often includes intact or fragmented gene sequences, and exhibits high copy number variation. Recent studies have shown that oncogene amplification on ecDNA is prevalent in many cancer types. This illustrates the significance of its role in the development and progression of cancer. Furthermore, ecDNA can induce drug resistance and adversely affect patient prognosis via various mechanisms, demonstrating considerable biological and potential therapeutic significance in preclinical investigations. This review outlines the key characteristics of ecDNA, analyzes its role in carcinogenesis and drug resistance, and evaluates current detection methods, aiming to explore its potential as a therapeutic target in cancer treatment.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124223"},"PeriodicalIF":5.1,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146052701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reversible ubiquitination regulates HSF1 phase separation in response to proteotoxic stress","authors":"Yue Zhu ,&nbsp;Jianhua Wang ,&nbsp;Shuhong Tang ,&nbsp;Zhiqiang Li ,&nbsp;Ruilin Wang ,&nbsp;Peng Wang ,&nbsp;Jiayu Li ,&nbsp;Shaoxuan Cheng ,&nbsp;Han Liu ,&nbsp;Yingqiu Zhang ,&nbsp;Zhaoxia Dai ,&nbsp;Qitao Yan ,&nbsp;Shuyan Liu","doi":"10.1016/j.lfs.2026.124224","DOIUrl":"10.1016/j.lfs.2026.124224","url":null,"abstract":"<div><h3>Aims</h3><div>Heat shock factor 1 (HSF1) undergoes phase separation to form nuclear condensates in response to proteotoxic stress, which governs cell fate. Protein ubiquitination is a widely existed post-translational modification and closely participated in liquid-liquid phase separation. However, the exact roles of ubiquitination in HSF1 condensation remain obscure. Here, we aimed to investigate the regulation of HSF1 phase separation by ubiquitination in cells under proteotoxic conditions.</div></div><div><h3>Materials and methods</h3><div>Endogenous and exogenous HSF1 condensate formation was detected by immunofluorescence assays. HSF1 phase separation properties were analyzed by fluorescence recovery after photobleaching (FRAP) analysis. Western blotting, immunofluorescence, immunoprecipitation and co-transfection assays were performed to identify E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) regulating HSF1 phase separation. The influence of ubiquitination sites on HSF1 phase separation was investigated by site-directed mutagenesis.</div></div><div><h3>Key findings</h3><div>Proteasome inhibitor PS341 induced HSF1 to form nuclear phase-separated condensates in a time-dependent manner. E3 ubiquitin ligase STUB1 promoted the phase separation of HSF1 by enhancing HSF1 ubiquitination, while DUBs USP13 and ATXN3 negatively regulated HSF1 condensation. Mutations of all nine ubiquitination sites within HSF1 dramatically inhibited condensate formation, with single-site mutations also showing significantly attenuated phase separation.</div></div><div><h3>Significance</h3><div>Ubiquitination at multiple lysine residues jointly drives HSF1 phase separation in cells exposed to proteotoxic stress, which is coordinately regulated by E3 ubiquitin ligase STUB1 and DUBs including USP13 and ATXN3.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124224"},"PeriodicalIF":5.1,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}