Life sciences最新文献

{"title":"Angiopoietin-2-mediated integrin α5β1 and FAK signaling contributes to pulmonary arterial hypertension pathogenesis.","authors":"Shifan Chen, Jialing Yin, Zhiwei Kan, Xiaoli Li, Mingyu Yang, Huiting Chen, HongYu Chen, Sijia Li, Wei Huang, Xiufeng Yu","doi":"10.1016/j.lfs.2026.124441","DOIUrl":"https://doi.org/10.1016/j.lfs.2026.124441","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by pulmonary vascular remodeling and right heart failure, in which endothelial dysfunction plays a central role. Angiopoietin-2 (ANGPT2) has been implicated in endothelial injury and vascular remodeling in multiple diseases; however, its role in hypoxic PAH remains incompletely understood. This study investigated the role and underlying mechanisms of ANGPT2 in PAH, with a particular focus on endothelial integrity, permeability, and vascular remodeling. Gene expression profiling was performed using lung tissues from patients with PAH, and ANGPT2 expression was further evaluated in plasma and lung tissues. Its functional role was examined in hypoxia-induced and Sugen/hypoxia (SuHx)-induced animal models of PAH. The effects of ANGPT2 inhibition by AAV-shANGPT2 delivery on hemodynamics, right ventricular function, and vascular remodeling were assessed. In vitro, pulmonary artery endothelial cells (PAECs) were used to evaluate the effects of ANGPT2 on proliferation, migration, and extracellular matrix remodeling. ANGPT2 expression was significantly increased in patients with PAH and in experimental models, and its levels correlated with indices of disease severity. Inhibition of ANGPT2 attenuated pulmonary hypertension, reduced right ventricular hypertrophy, and ameliorated pulmonary vascular remodeling, including collagen deposition and small-vessel muscularization. In PAECs, ANGPT2 inhibition restored impaired migration and tube formation and attenuated hypoxia-induced cell cycle progression. Mechanistically, ANGPT2 regulated integrin expression and activated focal adhesion kinase (FAK) signaling, thereby influencing endothelial adhesion, migration, and extracellular matrix remodeling. Collectively, these findings identify ANGPT2 as an important mediator of pulmonary vascular remodeling in experimental PAH and support ANGPT2 inhibition as a potential therapeutic approach warranting further preclinical investigation.</p>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":" ","pages":"124441"},"PeriodicalIF":5.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856570","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":"Targeting the AMPK/ACC pathway with luteolin suppresses de novo lipogenesis and limits tumor burden in a MASH-HCC mouse model.","authors":"Gaoxuan Shao, Chenceng Sun, Chenhao Ye, Ying Liu, Jiashu Pan, Yujing Liu, Lu Lu, Lei Wang, Zemin Lin, Fan Yang, Guang Ji, Hanchen Xu","doi":"10.1016/j.lfs.2026.124440","DOIUrl":"https://doi.org/10.1016/j.lfs.2026.124440","url":null,"abstract":"<p><strong>Aims: </strong>Metabolic dysfunction-associated steatohepatitis (MASH) is a primary driver of hepatocellular carcinoma (HCC), yet effective therapeutic interventions remain limited. While luteolin is known for its anti-inflammatory properties, its efficacy and underlying mechanism in the MASH-HCC transition are not fully understood. This study investigated the protective effects of luteolin against MASH-HCC and the role of the AMPK/ACC signaling pathway in this process.</p><p><strong>Materials and methods: </strong>In vivo, a MASH-HCC mouse model was established using diethylnitrosamine (DEN) combined with a high-fat, high-cholesterol (HFHC) diet. Mice were treated with vehicle or luteolin (50 or 100 mg/kg) for 26 weeks. Progression was monitored via serum alpha-fetoprotein (AFP), histological analysis, and Western blotting. In vitro, HepG2 and Huh-7 cells were challenged with cholesterol and treated with luteolin. The AMPK inhibitor BAY-3827 was employed to verify whether the metabolic benefits of luteolin were pathway-dependent.</p><p><strong>Key findings: </strong>Luteolin treatment significantly reduced tumor burden, lowered serum AFP levels, and attenuated hepatic lipid accumulation and fibrosis in MASH-HCC mice. In vitro results mirrored these findings, showing that luteolin reduced cholesterol-induced lipid loading. Mechanistically, luteolin increased the phosphorylation of AMPK and its downstream target, ACC. Furthermore, pharmacological inhibition of AMPK with BAY-3827 abolished the lipid-lowering effects of luteolin in hepatic cells, confirming that its therapeutic benefits are mediated through AMPK activation.</p><p><strong>Significance: </strong>Luteolin suppresses the progression of MASH to HCC by activating the AMPK/ACC signaling pathway and subsequently inhibiting de novo lipogenesis. These findings highlight luteolin as a promising potential therapeutic candidate for the prevention and treatment of MASH-related liver cancer.</p>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":" ","pages":"124440"},"PeriodicalIF":5.1,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839835","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":"Expression of Concern: Anti-apoptotic and neurogenic properties in the hippocampus as possible mechanisms for learning and memory improving impacts of vitamin D in hypothyroid rats during the growth period [Life Sciences 312 (2023) 121209].","authors":"","doi":"10.1016/j.lfs.2026.124278","DOIUrl":"10.1016/j.lfs.2026.124278","url":null,"abstract":"","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"392 ","pages":"124278"},"PeriodicalIF":5.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490899","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":"Calycosin attenuates renal fibrosis by modulating lipid metabolism via the PCK1/TWIST1/CPT1α axis.","authors":"Ziyi Qu, Zhongtang Li, Yilin Wang, Beibei Jiang, Jiahui Liu, Riming He, Shudong Yang","doi":"10.1016/j.lfs.2026.124423","DOIUrl":"https://doi.org/10.1016/j.lfs.2026.124423","url":null,"abstract":"<p><strong>Aims: </strong>Renal lipid metabolic dysregulation drives tubular injury and fibrosis in chronic kidney disease (CKD), yet endogenous targets governing tubular lipid homeostasis remain incompletely understood. This study aimed to elucidate how calycosin (CAL), an O-methylated isoflavone from Astragali Radix, corrects renal lipid metabolic dysregulation and attenuates fibrosis in CKD.</p><p><strong>Materials and methods: </strong>An adenine-induced CKD mouse model and TGF-β1-stimulated HK-2 cells were treated with CAL. Lipidomics and network pharmacology screened candidate targets. Surface plasmon resonance (SPR) and molecular dynamics simulation validated target binding. Adeno-associated virus (AAV)-mediated renal phosphoenolpyruvate carboxykinase 1 (PCK1) overexpression in vivo and lentiviral overexpression in vitro established the regulatory relationship. The PCK1 inhibitor 3-mercaptopicolinic acid served as reverse validation.</p><p><strong>Key findings: </strong>CAL improved renal function, alleviated fibrosis, and reduced lipid deposition both in vivo and in vitro. Lipidomics revealed that CAL bidirectionally modulated renal lipid metabolism by suppressing glycerophospholipid, sphingolipid, and glycerolipid accumulation while restoring omega-3 PUFA-enriched lipids and decreasing lipid saturation. SPR confirmed direct binding of CAL to PCK1. Gain-of-function experiments demonstrated that PCK1 negatively regulates Twist family BHLH transcription factor 1 (TWIST1) in the kidney. Accordingly, CAL activated the PCK1/TWIST1/carnitine palmitoyltransferase 1 A (CPT1α) axis, restoring fatty acid oxidation and suppressing lipid uptake, thereby attenuating lipotoxicity-driven oxidative stress and tubular apoptosis.</p><p><strong>Significance: </strong>This study identifies PCK1 as an endogenous binding target of CAL in the kidney and delineates the PCK1/TWIST1/CPT1α axis as the downstream signaling circuitry through which CAL corrects tubular lipid metabolic disorders and attenuates renal fibrosis, providing mechanistic rationale for targeted CKD therapy.</p>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":" ","pages":"124423"},"PeriodicalIF":5.1,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816636","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":"Thioredoxin-1 attenuates atrial remodeling in pressure-overload heart failure by inhibiting SP1/TGF-beta/Smad signal.","authors":"Youfu Huang, Zhongda Chen, Yan Dong, Qiushi Chen, Yanjie Chen, Xuesheng Fan, Yan Hua, Wei Zhao, Ruiji Xu, Fengxiang Zhang","doi":"10.1016/j.lfs.2026.124417","DOIUrl":"https://doi.org/10.1016/j.lfs.2026.124417","url":null,"abstract":"<p><strong>Aims: </strong>Oxidative stress is a core pathological hallmark of pressure-overload heart failure (HF), and thioredoxin-1 (Trx1) exerts critical cytoprotective effects against oxidative injury. Here, we hypothesized that Trx1 downregulation in atrial fibroblasts contributes to elevated atrial fibrillation (AF) susceptibility in the setting of pressure-overload HF.</p><p><strong>Methods: </strong>To investigate Trx1's gain-of-function effects on atrial remodeling, we developed adeno-associated virus 9 (AAV9)-mediated atrial-specific Trx1-overexpressing mice. These mice underwent transverse aortic constriction (TAC) to induce pressure overload. Cardiac function and atrial fibroblasts were evaluated in both groups post-TAC. Conversely, Trx1 knockdown was performed to assess loss-of-function effects. Atrial tissue proteomic sequencing explored the underlying molecular mechanisms.</p><p><strong>Results: </strong>Bioinformatic analysis revealed significant Trx1 downregulation in cardiac tissues from patients with pressure-overload HF. In TAC mice, atrial Trx1 expression was markedly reduced, predominantly in atrial fibroblasts. Atrial-specific Trx1 overexpression in TAC-induced mice ameliorated HF phenotypes, attenuated atrial dilation, reduced atrial fibrosis by 15%, decreased AF incidence by 15%, and shortened AF episode duration by 80% versus empty vector controls. Conversely, atrial-specific Trx1 knockdown in TAC mice exacerbated HF, atrial dilation, and fibrosis (90% increase), with 17% higher AF incidence and doubled AF duration. Mechanistically, proteomic and validation assays revealed that Trx1 deficiency relieved its inhibitory effect on specificity protein 1 (SP1); upregulated SP1 enhanced TGF-β1 transcription and Smad family protein binding, thereby activating atrial fibroblasts and driving pathological atrial fibrosis.</p><p><strong>Conclusions: </strong>Trx1 alleviates pressure-overload TAC-induced atrial structural remodeling and reduces AF susceptibility via suppressing SP1 expression and inhibiting the TGF-β/Smad signaling cascade.</p>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":" ","pages":"124417"},"PeriodicalIF":5.1,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816714","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":"Sirtuin 1 inhibits NLRP3 inflammasome activation through protein-protein interaction","authors":"Li-Chun Ho ,&nbsp;Yi-Ling Tsang ,&nbsp;Hsiao-Chien Hung ,&nbsp;Yu-Hsing Chen ,&nbsp;Ching-Chun Yang ,&nbsp;Yi-Ning Cheng ,&nbsp;Yu-Ting Tu ,&nbsp;Ai-Ning Shao ,&nbsp;Pei-Jane Tsai ,&nbsp;Yi-Che Lee ,&nbsp;Hsi-Hao Wang ,&nbsp;Shih-Yuan Hung ,&nbsp;Yau-Sheng Tsai","doi":"10.1016/j.lfs.2026.124260","DOIUrl":"10.1016/j.lfs.2026.124260","url":null,"abstract":"<div><div>Sirtuin 1 (SIRT1) is known to suppress NLRP3 inflammasome activation via NF-κB inhibition, but its role in inflammasome assembly remains unclear. Here, using a HEK293T reconstitution system, we show that SIRT1 directly interacts and co-localizes with NLRP3 upon inflammasome activation. SIRT1 co-expression disrupts NLRP3-ASC interaction and NLRP3-dependent ASC oligomerization, thereby impairing inflammasome assembly. Co-immunoprecipitation analyses reveal that the N-terminus of SIRT1 is essential for binding and inhibitory function, whereas its deacetylase activity is dispensable. These findings highlight that SIRT1 suppresses NLRP3 inflammasome activation primarily through protein–protein interaction rather than deacetylation, suggesting a potential basis for targeting NLRP3–SIRT1 interaction in inflammasome-related diseases.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"390 ","pages":"Article 124260"},"PeriodicalIF":5.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135656","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":"Role of miR-338-3p and miR-378a-3p as regulators in Crohn's disease pathogenesis: Potential therapeutic implications in inflammatory bowel disease","authors":"Ki-Uk Kim ,&nbsp;Jung Min Moon ,&nbsp;Eunsu Lim ,&nbsp;Kang-Bin Dan ,&nbsp;Jeongkuk Seo ,&nbsp;Kyuwon Kim ,&nbsp;Seung Yong Shin ,&nbsp;Hyeyoung Min ,&nbsp;Chang Hwan Choi","doi":"10.1016/j.lfs.2026.124217","DOIUrl":"10.1016/j.lfs.2026.124217","url":null,"abstract":"<div><h3>Aims</h3><div>Epithelial cell-derived microRNAs (miRNAs) are increasingly recognized as contributors to inflammatory bowel disease (IBD) through altered epithelial permeability and inflammatory cytokine production. This prospective study compared epithelial miRNA expression in Crohn's disease (CD) patients and healthy controls, and investigated their immunoregulatory role in experimental IBD models</div></div><div><h3>Materials and methods</h3><div>Terminal ileum samples were collected via ileocolonoscopy from healthy controls and CD patients (remission and active state). Small-RNA sequencing identified unique miRNA profiles, including miR-338-3p and miR-378a-3p, validated by qRT-PCR. In dextran sodium sulfate-induced colitis mice, mimics were administered, and disease severity, gene expression, and immune cell infiltration were assessed by clinical, histological, and molecular assays</div></div><div><h3>Key findings</h3><div>miR-338-3p/miR-378a-3p mimics reduced disease activity scores, attenuated colon shortening, and decreased Th17 cell infiltration in colonic tissues. Histological and immunohistochemical analyses confirmed improved tissue integrity and reduced macrophage/T-cell infiltration in the colon. Mechanistically, miR-338-3p targeted <em>MACC1</em>, while miR-378a-3p suppressed <em>IL33</em>, a proinflammatory cytokine linked to CD pathogenesis.</div></div><div><h3>Significance</h3><div>The results underscore the distinct features of miR-338-3p and miR-378a-3p in CD mucosa and suggest their therapeutic potential for modulating immune responses in CD</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124217"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041020","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":"2026-03-15","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":"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":"2026-03-15","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":"ERCC6L promotes cutaneous melanoma progression via PLK1-mediated aerobic glycolysis: Mechanisms and therapeutic implications","authors":"Mengdi Zhang ,&nbsp;Shengbo Zhou ,&nbsp;Bing Han ,&nbsp;Yining Ge","doi":"10.1016/j.lfs.2026.124216","DOIUrl":"10.1016/j.lfs.2026.124216","url":null,"abstract":"<div><h3>Aims</h3><div>To elucidate the oncogenic role and mechanistic basis of ERCC6L in cutaneous melanoma, focusing on its impact on tumor metabolism and progression.</div></div><div><h3>Materials and methods</h3><div>Multi-omics bioinformatics analysis of public datasets (GEO, TCGA) defined the clinical relevance of ERCC6L. <em>In vitro</em> functional assays (CCK-8, colony formation, Transwell, flow cytometry) were performed in melanoma cell lines following genetic manipulation. Mechanistic studies employed gene set enrichment analysis, chromatin immunoprecipitation-quantitative PCR, dual-luciferase reporter assays, western blotting, and metabolic flux analysis. The functional significance of the ERCC6L-PLK1 axis was validated in an NSG mouse subcutaneous xenograft model.</div></div><div><h3>Key findings</h3><div>ERCC6L is significantly upregulated in melanoma tissues, and its high expression is an independent prognostic factor for poor survival. Genetic ablation of ERCC6L potently inhibited melanoma cell proliferation, migration, invasion, and tumor growth, while promoting apoptosis. Mechanistically, <em>ERCC6L</em> transcriptionally activates <em>PLK1</em> by directly binding to its promoter. This ERCC6L-PLK1 axis drives aerobic glycolysis (the Warburg effect), upregulating key glycolytic enzymes (GLUT1, LDHA, PKM2, HK2) and enhancing lactate production and ATP generation. Crucially, PLK1 inhibition or glycolysis blockade effectively reversed the tumor-promoting phenotypes induced by ERCC6L.</div></div><div><h3>Significance</h3><div>Our study identifies <em>ERCC6L</em> as a novel upstream transcriptional regulator of <em>PLK1</em> that fuels melanoma progression by reprogramming glucose metabolism. The ERCC6L-PLK1-glycolysis axis represents a promising prognostic biomarker and a potential therapeutic target for cutaneous melanoma.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124216"},"PeriodicalIF":5.1,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018876","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}