Life sciences最新文献

{"title":"Cardiomyocyte-specific activation of the sarcomere-localized Dnajb6b chaperone causes cardiomyopathy and heart failure through upregulated sarcoplasmic reticulum stress","authors":"Yuting Liu ,&nbsp;Yajie Jiang ,&nbsp;Taiwei Ma ,&nbsp;Wenjing Dong ,&nbsp;Peng Yang ,&nbsp;Lixia Peng ,&nbsp;Baokun Wang ,&nbsp;Chuanhong Wu ,&nbsp;Zhiqiang Li ,&nbsp;Hong Zhang ,&nbsp;Yuanchao Sun ,&nbsp;Yujuan Niu ,&nbsp;Yonghe Ding","doi":"10.1016/j.lfs.2025.123711","DOIUrl":"10.1016/j.lfs.2025.123711","url":null,"abstract":"<div><h3>Aims</h3><div>Despite abundant expression of <em>DNAJB6</em> gene in the heart, its roles in cardiac diseases remain underexplored. We aimed to investigate the function of its zebrafish (<em>Danio rerio</em>) ortholog, the <em>dnajb6b</em> gene, in cardiomyopathy and heart failure.</div></div><div><h3>Materials and methods</h3><div>Both loss-of-function mutation and gain-of-function transgenic approaches were employed in zebrafish. High frequency echocardiography was performed to evaluate cardiac function indices in adult zebrafish. 4-phenylbutyric acid (4-PBA) was used to pharmacologically inhibit sarcoplasmic reticulum (SR) stress in zebrafish. Western blot was carried out to determine expression of DNAJB6 isoforms in human patients' heart tissues.</div></div><div><h3>Key findings</h3><div>Global loss-of-function mutations affecting both the sarcomere-localized short (Dnajb6b[S]) and nucleus-localized long (Dnajb6b[L]) isoforms appeared phenotypically normal. In contrast, cardiomyocyte-specific overexpression of a truncated, sarcomere-localized Dnajb6b(L) isoform (Dnajb6b[∆L]) led to severe cardiomyopathy and heart failure phenotypes. Mechanistically, Dnajb6b responded to sarcoplasmic reticulum (SR) stress and activation of Dnajb6b(∆L) resulted in elevated SR stress, accumulation of ubiquitinated protein aggregation, and aberrant activation of autophagy. 4-PBA treatment partially rescued cardiac dysfunction and extended the lifespan of zebrafish with cardiomyocyte-specific activation of Dnajb6b(∆L). Finally, elevated expression of both DNAJB6(S<em>)</em> and DNAJB6(L) isoforms was detected in failing human hearts, supporting their clinical relevance.</div></div><div><h3>Significance</h3><div>Gain-of-function mutation in Dnajb6b(∆L) isoform causes cardiomyopathy and heart failure, likely mediated by elevated SR stress. This study enhances our understanding of Dnajb6's role in cardiac proteostasis and highlights its potential as a therapeutic target for the treatment of cardiomyopathy and heart failure.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"374 ","pages":"Article 123711"},"PeriodicalIF":5.2,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935289","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":"Epithelial cells and fibroblasts are both activated via TGF-β1 and GSK-3β pathways differentially in the comorbidity of pulmonary fibrosis with lung adenocarcinoma","authors":"Chenguang Yang ,&nbsp;Zijian Qin ,&nbsp;Hu Ma ,&nbsp;Huanqin Liu ,&nbsp;Mengdan Hou ,&nbsp;Jing Wei ,&nbsp;Hongyan Guo ,&nbsp;Xiang An ,&nbsp;Feng Yang ,&nbsp;Aijun Yang ,&nbsp;Yamei Dang ,&nbsp;Fangfang Zhang","doi":"10.1016/j.lfs.2025.123696","DOIUrl":"10.1016/j.lfs.2025.123696","url":null,"abstract":"<div><h3>Aims</h3><div>Pulmonary fibrosis (PF) is always exacerbated by the comorbidity of lung adenocarcinoma (LUAD), and patients frequently died from the complications of PF instead of lung cancer. Although many studies have unveiled the mechanisms underlying PF exacerbation due to lung cancer resection and radiotherapy, the influence of lung cancer itself on PF remains enigmatic.</div></div><div><h3>Materials and methods</h3><div>We cocultivated mouse pulmonary cells with mouse LUAD cells to explore the influence of LUAD on the pathogenesis and progression of PF. Additionally, a comorbidity model of PF with LUAD was established in mice via intratracheal injection of bleomycin (BLM) followed by in situ transplantation of LUAD cells. Furthermore, immunofluorescence, immunohistochemistry, and molecular analyses were employed to elucidate the mechanisms underlying the exacerbation of PF by the comorbidity of LUAD.</div></div><div><h3>Key findings</h3><div>We found that PF was significantly exacerbated by LUAD. In the microenvironment of LUAD, the epithelial-mesenchymal transition (EMT) was predominantly activated in lung epithelial cells, while the transformation of lung fibroblasts into myofibroblasts was markedly induced. The TGF-β and GSK-3β pathways were differentially activated in lung epithelial cells and fibroblasts. Furthermore, clinical samples confirmed the involvement of these pathways in the process of PF exacerbation induced by LUAD in patients' lung lesions of PF with LUAD.</div></div><div><h3>Significance</h3><div>This study initially reveals that LUAD exacerbates PF by modulating epithelial cells and fibroblasts through TGF-β and GSK-3β pathways differentially. Practically, targeting the pathways of TGF-β and GSK-3β may promise a potential strategy for the prophylaxis of PF exacerbation in patients with LUAD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"374 ","pages":"Article 123696"},"PeriodicalIF":5.2,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929086","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":"Impact of mSWI/SNF epigenetic complexes on ionizing radiotherapy resistance in malignant diseases: A comprehensive view in oncology","authors":"Octavio Augusto Trejo-Villegas ,&nbsp;Enrique Pérez-Cárdenas ,&nbsp;Federico Maldonado-Magos ,&nbsp;Federico Ávila-Moreno","doi":"10.1016/j.lfs.2025.123690","DOIUrl":"10.1016/j.lfs.2025.123690","url":null,"abstract":"<div><div>The mSWI/SNF chromatin remodeling complexes are critical regulators of genomic stability, particularly in their role in orchestrating DNA repair and modulating cellular responses to ionizing radiation therapy. Their involvement has positioned these molecular complexes as key factors in determining radiosensitivity in human malignant diseases. The present review delves into the biomedical contributions of specific mSWI/SNF subunits, including ARID1A, SMARCB1, SMARCA4, PBRM1, and BRD9, highlighting their pivotal roles in influencing tumor responses to radiotherapy. Evidence suggests that the loss of function in these subunits, often due to mutations, disrupts DNA repair pathways, thereby compromising genomic integrity and enhancing susceptibility to radiation-induced damage. Emerging preclinical studies have underscored the potential of exploiting these vulnerabilities through pharmacological targeting of mSWI/SNF complexes. Inhibition of these complexes can impair DNA damage repair mechanisms, creating a synthetic lethality effect by using a combined epigenetic therapy with ionizing radiation protocols. This dual approach not only amplifies the therapeutic efficacy of radiotherapy but also broadens the spectrum of potential strategies for oncological therapy. However, further investigation into the molecular mechanisms underlying these epigenetic interactions is essential for optimizing oncological therapies and paving the way for clinical applications aimed at enhancing radiotherapy outcomes in cancer patients.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"374 ","pages":"Article 123690"},"PeriodicalIF":5.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929070","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":"FoxM1 promotes the proliferation of cervical adenocarcinoma cells through transcriptional activation of FAM83D","authors":"Kaijia Tu ,&nbsp;Zhimei Luo ,&nbsp;Lan Yi ,&nbsp;Zengming Li ,&nbsp;Youkun Jie ,&nbsp;Longyu Li ,&nbsp;Yunna Qin ,&nbsp;Ziyu Zhang","doi":"10.1016/j.lfs.2025.123691","DOIUrl":"10.1016/j.lfs.2025.123691","url":null,"abstract":"<div><div>Cervical adenocarcinoma exhibits a steadily increasing global incidence with notable demographic shifts toward younger populations. Despite the absence of distinct clinical guidelines differentiating its management from squamous cell carcinoma, treatment strategies remain non-specific, contributing to suboptimal patient outcomes. To address this therapeutic gap, we systematically investigated molecular disparities between adenocarcinoma and squamous cell carcinoma through integrated ChIP-seq and RNA-seq analyses. Our multi-omics approach identified FAM83D as a novel transcriptional target directly regulated by the FoxM1 oncoprotein, demonstrating adenocarcinoma-specific expression in HeLa cells. This regulatory relationship was experimentally validated using quantitative PCR and luciferase reporter assays. Mechanistically, we delineated that FoxM1 governs cell cycle progression and proliferation via FAM83D-dependent pathways. Intriguingly, co-immunoprecipitation studies revealed a physical interaction between FoxM1 and karyopherin α2 (KPNA2), another adenocarcinoma-enriched protein, with their expression levels showing significant positive correlation in clinical specimens. This study not only elucidates the oncogenic axis of FoxM1-FAM83D but also reveals the dual regulatory role of FoxM1 as both a transcriptional activator and protein interaction hub in cervical adenocarcinoma pathogenesis. These findings expand the molecular landscape of this malignancy and identify potential therapeutic entry points for targeted adenocarcinoma interventions.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"374 ","pages":"Article 123691"},"PeriodicalIF":5.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929073","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":"Umbilical cord-derived mesenchymal stem cells secretomes promote embryo development and implantation","authors":"Prompunya Teerapong ,&nbsp;Yuan-Ting Yang ,&nbsp;Dilip Bhargava Sreerangaraja Urs ,&nbsp;Jun-Jen Liu ,&nbsp;Shu-Huei Kao","doi":"10.1016/j.lfs.2025.123693","DOIUrl":"10.1016/j.lfs.2025.123693","url":null,"abstract":"<div><h3>Aims</h3><div>Successful implantation relies on high-quality blastocysts, uterine receptivity, and effective embryo-endometrium communication. This study investigated the effects of umbilical cord-derived mesenchymal stem cells (UC-MSC) secretomes on embryo development and implantation.</div></div><div><h3>Main methods</h3><div>Trophoblastic spheroids and murine embryos were used to evaluate the impact of UC-MSC secretomes. Embryos obtained through superovulation were cultured <em>in vitro</em> and divided into five groups: a control group and four experimental groups treated with varying concentrations of UC-MSC secretomes (2.5, 5, 10, and 50 μg/mL). Embryo development competence and implantation potential were assessed in each group, and the expression levels of related genes were analyzed.</div></div><div><h3>Key findings</h3><div>Supplementation with UC-MSC secretomes significantly enhanced trophoblast cell migration. It also stimulated endometrial cell proliferation and upregulated key implantation-related genes (<em>LIF</em>, <em>LIFR</em>, <em>VEGFA</em>, <em>ITGB3</em>, and <em>ITGAV</em>), improving endometrial receptivity and adhesion in trophoblastic spheroid co-cultures. While morulation rates of murine embryos remained unchanged, UC-MSC secretomes supplement significantly increased blastulation, pluripotency gene expression, and hatching rates. Supplementation with 10 and 50 μg/mL significantly increased blastocyst diameter and blastomere number, as well as embryo adhesion, outgrowth areas, and implantation rates. Additionally, growth factor analysis showed elevated VEGF-A and PDGF-AA levels in the culture media.</div></div><div><h3>Significance</h3><div>This study demonstrates that UC-MSC secretomes enhance both embryo development and endometrial cell function, facilitating implantation potential. These findings suggest their potential utility in supporting preimplantation embryos and improving maternal endometrial receptivity in ART.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"374 ","pages":"Article 123693"},"PeriodicalIF":5.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929075","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":"Epigenetic alterations and microbiota changes in the saliva of individuals with binge-eating spectrum disorders compared with normal weight healthy controls","authors":"Francesca Mercante ,&nbsp;Afrouz Abbaspour ,&nbsp;Mariangela Pucci ,&nbsp;Annalaura Sabatucci ,&nbsp;Marianna Rania ,&nbsp;Fani Konstantinidou ,&nbsp;Valentina Gatta ,&nbsp;Liborio Stuppia ,&nbsp;Carlo Cifani ,&nbsp;Cynthia M. Bulik ,&nbsp;Cristina Segura-Garcia ,&nbsp;Claudio D'Addario","doi":"10.1016/j.lfs.2025.123695","DOIUrl":"10.1016/j.lfs.2025.123695","url":null,"abstract":"<div><h3>Aims</h3><div>Binge-eating spectrum disorders, including bulimia nervosa (BN) and binge-eating disorder (BED), have psychological, behavioral, and physical effects, which present significant challenges for accurate diagnosis and treatment. Identifying biomarkers is thus of relevance to improve diagnostic and treatment strategies.</div></div><div><h3>Main methods</h3><div>Saliva collected from female individuals with BED (<em>n</em> = 20), BN (<em>n</em> = 17), and normal weight healthy controls (NW-HC) (n = 20) was analyzed to assess salivary microbiome, exosomal miRNA expression, and DNA methylation of dopaminergic system gene components.</div></div><div><h3>Key findings</h3><div>Microbial diversity was significantly reduced in BED and BN groups compared to NW-HC. Differential abundance analysis revealed that Bacilli (class-level) were enriched in BN and BED, while Lachnospirales (order-level) were significantly depleted in BN compared to NW-HC. In total, 79 miRNAs were differentially expressed in patients compared with controls. Alteration in four of these miRNAs (<em>let-7b-5p</em>, <em>mir-15b-5p</em>, <em>mir-429</em>, and <em>mir-221-3p</em>) identified via network analysis as potentially relevant to psychiatric disorders, were confirmed to be significantly upregulated in both BED and BN compared with controls. Significant hypomethylation at specific CpG sites of the <em>DAT1</em> gene was also observed in BED and BN groups relative to controls. Correlation analysis highlighted significant associations between specific microbiota genera, miRNA expression, and DNA methylation of <em>DAT1</em> in both the BED and BN groups.</div></div><div><h3>Significance</h3><div>Our findings provide new evidence on the role of epigenetic modifications linked to alterations in salivary microbial composition and diversity in BED and BN, opening new avenues for future research and therapeutic interventions in eating disorders targeting miRNAs and microbiota.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"374 ","pages":"Article 123695"},"PeriodicalIF":5.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929074","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":"MEIS1: From functional versatility to post-transcriptional/translational regulation","authors":"Salma A. Fahim ,&nbsp;Shereen Ahmed El Sobky ,&nbsp;Ahmed Abdellatif ,&nbsp;Injie Omar Fawzy ,&nbsp;Ahmed Ihab Abdelaziz","doi":"10.1016/j.lfs.2025.123683","DOIUrl":"10.1016/j.lfs.2025.123683","url":null,"abstract":"<div><div>Myeloid ecotropic virus insertion site 1 (MEIS1) is a transcription factor involved in a myriad of functions such as hematopoiesis, cardiac regeneration, cell cycle progression, and limb and organ development. Its functional versatility extends beyond developmental biology, as aberrant MEIS1 expression has been implicated in various pathological contexts like carcinogenesis, cardiomyopathies, and neurodegenerative disorders. Recent advances in the field have uncovered novel layers of MEIS1 regulation, focusing on post-transcriptional and translational mechanisms, which collectively fine-tune its activity, stability, and subcellular localization. These include chromatin remodeling, epigenetic modifications in the enhancer and promoter regions, and protein modifications like phosphorylation and ubiquitination. The sophisticated regulation of MEIS1 including its interplay with non-coding RNAs (ncRNAs), either being an upstream or downstream of ncRNAs, equally represents an important regulatory mechanism orchestrating <em>MEIS1</em> expression and function. This review explores the multifaceted roles of MEIS1, emphasizing its dynamic regulatory networks and their implications in physiological and pathological conditions. It also provides forward-thinking guidance on the utilization of MEIS1 in targeted therapies across various clinical settings, highlighting its potential as a key regulatory factor in disease modulation and therapeutic innovation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"374 ","pages":"Article 123683"},"PeriodicalIF":5.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923701","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":"DBC1 promotes intervertebral disc degeneration by activating NF-κB pathway and inhibiting SIRT1 activity","authors":"Jiahao Lin ,&nbsp;Jiawei Ma ,&nbsp;Ze Wang,&nbsp;Cong Xu,&nbsp;Yun Sun,&nbsp;Zhimin Miao,&nbsp;Zexin Chen,&nbsp;Zeming Sun,&nbsp;Xiaolei Zhang,&nbsp;Yaosen Wu","doi":"10.1016/j.lfs.2025.123689","DOIUrl":"10.1016/j.lfs.2025.123689","url":null,"abstract":"<div><h3>Aims</h3><div>Intervertebral disc degeneration (IVDD) is a leading contributor to spinal degenerative diseases; however, its pathogenesis remains only partially elucidated. Recent studies have highlighted that the diminished activity of SIRT1 and the aberrant activation of the NF-κB signaling pathway are critical pathogenic factors in IVDD. DBC1 has been identified as a regulator of SIRT1 activity and the NF-κB signaling pathway. This study aimed to investigate the role of DBC1 in IVDD.</div></div><div><h3>Materials and methods</h3><div>The expression levels of DBC1 in the nucleus pulposus of aging rats were quantified. Both overexpression and knockdown of DBC1 were utilized to explore their effects on the extracellular matrix (ECM) of the nucleus pulposus. Furthermore, the influence of DBC1 on cellular senescence, apoptosis, and ECM regulation in nucleus pulposus cells was assessed using Western blot (WB), cellular fluorescence assays, and histological staining techniques.</div></div><div><h3>Key findings</h3><div>Our results demonstrate that DBC1 expression is significantly upregulated in IVDD. Moreover, DBC1 appears to contribute to IVDD by promoting apoptosis, senescence, and ECM degradation in nucleus pulposus cells. Mechanistic investigations revealed that DBC1 activates the NF-κB signaling pathway while suppressing SIRT1 expression in nucleus pulposus cells, suggesting that these two mechanisms underlie its effects on IVDD.</div></div><div><h3>Significance</h3><div>In summary, this study provides evidence that DBC1 may play a pivotal role in the pathogenesis of IVDD by inhibiting SIRT1 activity and activating the NF-κB signaling pathway. Consequently, targeting DBC1 suppression could represent a promising therapeutic strategy for managing IVDD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123689"},"PeriodicalIF":5.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143918276","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":"GSK621 ameliorates lipid accumulation via AMPK pathways and reduces oxidative stress in hepatocytes in vitro and in obese mice in vivo","authors":"Xiaoyu Wang ,&nbsp;GuangBing Li ,&nbsp;Jun Liu ,&nbsp;Wei Gong ,&nbsp;Ruixiao Li ,&nbsp;Jun Liu","doi":"10.1016/j.lfs.2025.123687","DOIUrl":"10.1016/j.lfs.2025.123687","url":null,"abstract":"<div><h3>Introduction</h3><div>Metabolic-dysfunction-associated fatty liver disease (MAFLD) represents a broad spectrum of liver lipid metabolism disorders associated with metabolic homeostasis, inflammation, oxidative stress, and fibrogenesis. The incidence of MAFLD has increased in recent years, but there is a lack of effective treatment strategies. GSK621 shows potential as a novel adenosine-monophosphate-activated protein kinase (AMPK) agonist; however, its function in lipid metabolism has not yet been confirmed.</div></div><div><h3>Objectives</h3><div>This study aimed to determine the effects of GSK621 on liver lipid accumulation <em>in vitro</em> and <em>vivo</em> and explore the underlying mechanism of these effects.</div></div><div><h3>Methods</h3><div>The function of GSK621 in lipid deposition was investigated <em>in vitro</em> with HepG2 cells and normal mouse liver cells (AML12), and <em>in vivo</em> using C57BL/6 J mice fed with a high-fat diet (60 % fat) for 8 weeks to establish a model of MAFLD, followed by GSK621 treatment for a further 8 weeks.</div></div><div><h3>Results</h3><div>GSK621 treatment significantly improved hepatocyte steatosis <em>via</em> the AMPK–carnitine palmitoyl transferase 1 (CPT1A) pathway and decreased levels of reactive oxygen species (ROS) in cells, accompanied by elevated expression of antioxidative stress proteins. MAFLD mice showed significant improvements in liver steatosis after GSK621 treatment, as well as increased expression of liver proteins related to the AMPK pathway and antioxidative stress.</div></div><div><h3>Conclusion</h3><div>GSK621 can improve hepatocytes steatosis <em>in vitro</em> and <em>vivo via</em> the AMPK–CPT1A pathway by increasing lipid metabolism and augmenting expression of antioxidant-stress-related proteins to reduce ROS deposition.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"374 ","pages":"Article 123687"},"PeriodicalIF":5.2,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923703","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":"Metal ions-induced programmed cell death: how does oxidative stress regulate cell death?","authors":"Xingsheng Wang,&nbsp;Zuohao Liu,&nbsp;Changjun Lin","doi":"10.1016/j.lfs.2025.123688","DOIUrl":"10.1016/j.lfs.2025.123688","url":null,"abstract":"<div><div>In recent years, the mechanisms of ferroptosis and cuproptosis, two novel modes of cell death, have been elucidated and have attracted much attention. Ferroptosis is dependent on the metabolic disruption of iron ions and lipid peroxidation, whereas cuproptosis is closely related to intracellular accumulation of copper ions, aggregation of lipoylated proteins and damage to Fe<img>S cluster proteins. In particular, oxidative stress plays an important role in both types of cell death. During ferroptosis, the central role of oxidative stress is reflected in the overproduction of reactive oxygen species (ROS) and lipid peroxidation of the cell membrane. Recent studies have revealed that ROS can propagate over long distances across cells in the form of trigger waves, triggering large-scale ferroptosis. In embryonic development, different regional redox states can limit the long-distance propagation of ferroptosis waves, which is critical for muscle remodeling and tissue formation during development. In cuproptosis, processes such as copper ions accumulation, tricarboxylic acid (TCA) cycle blockade, and reduced level of Fe<img>S cluster proteins are closely associated with oxidative stress. In addition, there is a close link between oxidative stress and death induced by other metal ions (Ca²⁺, Zn²⁺, etc.). In this paper, we review the role of oxidative stress in ferroptosis and cuproptosis and the related research progress to provide new ideas for understanding the mechanism of cell death and the occurrence and treatment of related diseases.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"374 ","pages":"Article 123688"},"PeriodicalIF":5.2,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929072","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}