Journal of molecular and cellular cardiology最新文献

{"title":"The RNA-binding protein Quaking is essential for cardiac homeostasis and function by regulating Morf4l2 splicing","authors":"Sunaina Kumari ,&nbsp;Shashi ,&nbsp;Sandhya Singh ,&nbsp;Abinash Swain ,&nbsp;Shakti Prakash ,&nbsp;Pragya Chitkara ,&nbsp;Rakesh Kumar Sharma ,&nbsp;Pratyush Agarwal ,&nbsp;Samprikta Kundu ,&nbsp;Aakash Gaur ,&nbsp;Renu Kumari ,&nbsp;Abhipsa Sinha ,&nbsp;Shambhabi Chatterjee ,&nbsp;Pankaj Prasun ,&nbsp;Oliver Hummel ,&nbsp;Bhaskar Pant ,&nbsp;Kinshuk Raj Srivastava ,&nbsp;Norbert Hübner ,&nbsp;Dipak Datta ,&nbsp;Kalyan Mitra ,&nbsp;Shashi Kumar Gupta","doi":"10.1016/j.yjmcc.2025.11.002","DOIUrl":"10.1016/j.yjmcc.2025.11.002","url":null,"abstract":"<div><h3>Background</h3><div>Lower levels of <em>Qki</em> were reported in human and mouse-failing hearts, implicating its involvement in cardiac diseases. However, the molecular and functional effects of its downregulation in adult myocardium remain largely unknown.</div></div><div><h3>Objective</h3><div>We aim to uncover the effects of <em>Qki</em> knockdown in adult hearts.</div></div><div><h3>Methods &amp; results</h3><div>Here we show that AAV9-mediated knockdown of <em>Qki</em> by shRNAs in the hearts of adult BALB/c mice led to cardiac malfunction, atrophy, apoptosis, heart failure, and death within two weeks. Global transcriptomic analysis of <em>Qki</em> knockdown hearts revealed significant dysregulation of 996 alternative splicing events upon <em>Qki</em> knockdown. Mechanistically, we discovered that loss of <em>Qki</em> promotes the exclusion of the third exon of <em>Morf4l2,</em> leading to higher expression of exon three excluded variant (<em>Morf4l2Δex3</em>). Like rodents, the RNA-seq dataset from 108 human hearts revealed a lower splice junction count of <em>MORF4L2</em> exon three in hearts with low levels of <em>QKI</em> compared to subjects with higher <em>QKI</em> levels. Specific knockdown of <em>Morf4l2Δex3</em> rescues <em>Qki</em> knockdown-induced cardiac cachexia and improves cardiac function. Moreover, <em>Morf4l2Δex3</em> was increased in the colon cancer-induced cardiac cachexia mouse model, and its inhibition prevented cardiac cachexia and improved cardiac function. Mechanistically, exon three of <em>Morf4l2</em> lies in the 5’UTR, and its exclusion leads to higher expression of MORF4L2 upon <em>Qki</em> knockdown due to the lack of a G2-quadruplex. Importantly, MORF4L2 protein sequence and localization were not affected by alternative splicing as exon three lies in the 5’UTR. We found that MORF4L2 is a chromatin-bound protein and regulates H3K27ac.</div></div><div><h3>Conclusion</h3><div><em>Qki</em> knockdown in the adult heart leads to cardiac cachexia due to the alteration of <em>Morf4l2</em> splicing. Inhibition of <em>Morf4l2Δex3</em> inhibits cancer-induced cardiac cachexia, demonstrating it as a potential therapeutic target.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 43-58"},"PeriodicalIF":4.7,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145489094","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":"Slit2-robo signaling regulates angiogenesis and repair following myocardial infarction","authors":"David Wong ,&nbsp;Matthew Tran ,&nbsp;Julie Martinez ,&nbsp;Itzetl Avila ,&nbsp;Adrian Arrieta ,&nbsp;Kyle Kalindjian ,&nbsp;Elle Rathbun ,&nbsp;Thomas M. Vondriska ,&nbsp;Eric M. Small ,&nbsp;Pearl Quijada","doi":"10.1016/j.yjmcc.2025.10.014","DOIUrl":"10.1016/j.yjmcc.2025.10.014","url":null,"abstract":"<div><div>The Slit2 guidance ligand and its Roundabout (Robo) family of receptors regulate axonal guidance and vascular patterning during cardiac morphogenesis, yet the role of Slit2-Robo signaling in the adult heart remains unclear. Here, we identified epicardium-derived Slit2 as highly enriched in neonatal cardiac fibroblasts (cFBs) but markedly reduced in adult hearts. Following myocardial infarction (MI), Slit2 transiently increases in the infarct border zone seven days post-MI but declines significantly after one month. In vitro, Slit2 overexpression in cFBs selectively upregulated angiogenic genes during myofibroblast differentiation without affecting extracellular matrix (ECM) gene expression. In vivo, AAV9-mediated cardiac-specific overexpression of Slit2 (AAV9-cTNT-Slit2) improved cardiac function, increased endothelial cell (EC) proliferation and vascular density, but did not alter fibrotic deposition following MI. Conditioned media from Slit2-overexpressing cFBs promoted EC proliferation, activation, and tube forming abilities, consistent with the increased expression of pro-angiogenic Robo1 and other vascular growth factors in the myocardium of AAV9-Slit2-treated hearts. Additionally, Slit2 overexpression attenuated cardiomyocyte hypertrophy after MI and suppressed fetal gene expression in vitro. Mechanistically, Slit2 appears to mediate its cardioprotective effects through enhanced interactions with Robo1 in cFBs and ECs. These findings support Slit2-Robo signaling as a promising therapeutic target for improving blood vessel formation and maintaining cardiac muscle integrity following ischemic injury.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 28-42"},"PeriodicalIF":4.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471032","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 influence of lactation on postpartum murine heart growth","authors":"Molly S. Kaissar ,&nbsp;Elnaz Ghajar-Rahimi ,&nbsp;Adalyn Meeks ,&nbsp;Arden Shen ,&nbsp;Yusheng Wu ,&nbsp;Craig J. Goergen ,&nbsp;Kyoko Yoshida","doi":"10.1016/j.yjmcc.2025.10.012","DOIUrl":"10.1016/j.yjmcc.2025.10.012","url":null,"abstract":"<div><div>The cardiovascular system adapts to meet rising physiological demands throughout pregnancy. Notably, the left ventricle grows to support this increased workload, which is thought to reverse after delivery. Yet, whether the heart returns to its pre-pregnant size, shape, and function postpartum is unclear. This postpartum cardiac recovery has been historically studied in rodents. However, despite previous research showing that postpartum-specific conditions like lactation affect hemodynamics and heart weight, the relationship between these hemodynamic changes and cardiac growth remains unclear. In this study, we investigate the impact of lactation on postpartum cardiac recovery. We monitored changes in left ventricular mass, volume, and function throughout pregnancy and postpartum in mice using 4D cardiac ultrasound in animals allowed to nurse their pups for 21 days postpartum and in those whose pups were removed immediately after delivery. We analyzed the relationship between the observed hemodynamics and heart growth in these mice using an existing multiscale computational model of heart growth. Here, we observe that pregnancy-induced cardiac hypertrophy reverses by one week postpartum in non-lactating mice but continues increasing after delivery in lactating mice. Our computational analysis suggests that hemodynamic and biological factors have distinct but complementary roles in driving postpartum growth. Further, our animal-specific simulations indicate that individual hemodynamic changes contribute to the observed variability in experimental heart growth, particularly throughout lactation. Overall, this study provides a detailed timeline of cardiac hypertrophy during and after pregnancy, emphasizes the significance of lactation status on postpartum recovery, and highlights the importance of hemodynamics to this phenomenon.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 1-11"},"PeriodicalIF":4.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431690","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":"Homocysteine activates endothelial TP receptor to promote von Willebrand factor secretion and thrombosis","authors":"Jiachen Zhang ,&nbsp;Xinyu Jia ,&nbsp;Ping Zhu ,&nbsp;Mengzheng Zhao ,&nbsp;Haodong Du ,&nbsp;Xinyi Yu ,&nbsp;Jing Huang ,&nbsp;Yegong Xie ,&nbsp;Yequn Chen ,&nbsp;Yi Zhu ,&nbsp;Qiankun Bao ,&nbsp;Jinlong He ,&nbsp;Liu Yao","doi":"10.1016/j.yjmcc.2025.10.013","DOIUrl":"10.1016/j.yjmcc.2025.10.013","url":null,"abstract":"<div><div>Hyperhomocysteinemia (HHcy), characterized by elevated plasma homocysteine (Hcy) levels, is a recognized risk factor for thrombosis and an independent contributor to acute coronary syndrome, although its underlying mechanisms are not fully understood. The current study is to investigate the impact of HHcy on arterial thrombosis and the underlying mechanisms. In this study, we established an HHcy mouse model using a high-methionine diet and found that HHcy significantly accelerated thrombosis. We identified that Hcy enhanced von Willebrand factor (vWF) secretion from endothelial cells, leading to increased FVIII-vWF binding and platelet adhesion. Moreover, we observed a significant positive correlation between vWF and Hcy levels in the plasma of 150 patients with acute coronary syndrome. Mechanistically, GPCR screening revealed that Hcy-induced increase in vWF levels was mediated by activating the thromboxane prostanoid receptor (TPr) on endothelial cells. Hcy might function as an endogenous ligand binding to TPr and subsequently activated the Gαq-PLC-Ca²⁺ pathway to promote vWF secretion. Pharmacological inhibition or endothelial-specific deletion of TPr effectively reduced plasma vWF levels and protected against HHcy-related thrombosis. Our findings underscored the pivotal role of TPr in mediating Hcy-induced procoagulant states and suggested that targeting the TPr signaling pathway could be a promising therapeutic strategy for treating HHcy-related thrombosis.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 59-71"},"PeriodicalIF":4.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145438335","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":"FABP4, marker of worse prognosis in cardiovascular disease, induces neutrophil's proatherogenic phenotype which is modulated by semaglutide","authors":"David Sánchez-López ,&nbsp;David García-Vega ,&nbsp;J.E. Viñuela ,&nbsp;Isabel Ferreirós-Vidal ,&nbsp;Diego Iglesias-Álvarez ,&nbsp;José Manuel Martínez-Cereijo ,&nbsp;Laura Reija-López ,&nbsp;Ángel L. Fernández-González ,&nbsp;José R. González-Juanatey ,&nbsp;Sonia Eiras","doi":"10.1016/j.yjmcc.2025.10.009","DOIUrl":"10.1016/j.yjmcc.2025.10.009","url":null,"abstract":"<div><div>Dysfunctional epicardial adiposity is a risk factor for coronary artery disease (CAD). Its genesis is associated with an upregulation of fatty acid binding protein 4 (FABP4) levels, which might exert paracrine inflammatory and atherogenic mechanisms on the cardiovascular system. We aimed to study the prognosis of patients with high systemic FABP4, its association with a neutrophil proatherogenic phenotype, involved mechanisms and its modulation by semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1ra). Higher plasma FABP4 levels than 50 ng/mL were associated with heart failure (HF) onset during follow-up. In patients with CAD, these levels were associated with pro-inflammatory and pro-atherogenic neutrophil profile markers as MPO, NGAL and CD11b, analysed by real-time PCR. The group of patients with the highest FABP4 levels exhibited higher levels of MMP9, CXCR2, and CD11b in neutrophils. A preclinical model, based on neutrophils and coronary endothelial cells, determined the effects of FABP4 on neutrophils' respiratory burst, by flow cytometry, activity of NF-κΒ, by western blot checking IκΒα phosphorylation, CD11b integrin expression levels and adhesion to coronary endothelial cells. A modulation of the neutrophils' transcriptome, analysed by RNA-seq, and plasma chemokine CCL5 levels suggested changes in leukocyte migration and platelet activation pathways in patients who reduced plasma FABP4 levels after semaglutide treatment. Thus, supraphysiological levels of FABP4 induce pro-inflammatory and proatherogenic mechanisms in neutrophils and coronary endothelial cells. Its modulation by semaglutide could explain its benefits on coronary artery disease (CAD).</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 12-27"},"PeriodicalIF":4.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145438161","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":"IGF-1 promotes cell surface expression of HCN4 pacemaker channels contributing to tachycardia","authors":"Nadine Erlenhardt ,&nbsp;Franziska Wohlfarth ,&nbsp;S. Erfan Moussavi-Torshizi ,&nbsp;Angela Koch ,&nbsp;Tobias Strasdeit ,&nbsp;Katharina Scherschel ,&nbsp;Ehsan Amin ,&nbsp;Max Anstötz ,&nbsp;Christian Meyer ,&nbsp;Nikolaj Klöcker","doi":"10.1016/j.yjmcc.2025.10.015","DOIUrl":"10.1016/j.yjmcc.2025.10.015","url":null,"abstract":"<div><div>Insulin-like growth factor 1 (IGF-1) controls cardiac growth, metabolism, and contractility. Whereas IGF-1 deficiency is associated with cardiovascular risk, the activation of its signal transduction may be cardioprotective after acute myocardial infarction. Clinical studies evaluate the therapeutic potential of systemic IGF-1 in disease conditions including heart failure, and reported tachycardia as a common side effect. Here, we demonstrate that IGF-1 accelerates cardiac pacemaking in an <em>ex vivo</em> mouse sinoatrial node preparation read out by optical voltage mapping. Heterologous reconstitution experiments in <em>Xenopus laevis</em> oocytes combining extracellular epitope tagging and electrophysiology reveal an increase in cell surface expression of the main cardiac pacemaker channel isoform HCN4 by IGF-1, which stimulates the Rab11-dependent endosomal recycling of the channel protein. In summary, the study not only adds to the modes of HCN channel regulation by growth factor signaling, but may also extend our understanding of arrhythmogenesis, commonly observed in consequence of IGF-1 dysregulation including cardiac hypertrophy.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 165-174"},"PeriodicalIF":4.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431685","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":"Molecular mechanisms of altered contraction with the β-myosin R403Q mutation in porcine ventricular muscle and a human stem cell-derived cardiomyocyte model","authors":"Sonette Steczina ,&nbsp;Saffie Mohran ,&nbsp;Matthew C. Childers ,&nbsp;Timothy S. McMillen ,&nbsp;Ateeqa Naim ,&nbsp;Matvey Pilagov ,&nbsp;Marica Dente ,&nbsp;Kristina B. Kooiker ,&nbsp;Christian Mandrycky ,&nbsp;Khushi Tawde ,&nbsp;Jennifer Hesson ,&nbsp;Jing Zhao ,&nbsp;Julie Mathieu ,&nbsp;J. Manuel Pioner ,&nbsp;Michael A. Geeves ,&nbsp;Weikang Ma ,&nbsp;Farid Moussavi-Harami ,&nbsp;Neil M. Kad ,&nbsp;Michael Regnier","doi":"10.1016/j.yjmcc.2025.10.008","DOIUrl":"10.1016/j.yjmcc.2025.10.008","url":null,"abstract":"<div><div>The R403Q mutation in the sarcomere protein beta-myosin heavy chain (β-MHC) is a known genetic cause of hypertrophic cardiomyopathy (HCM), associated with ventricular hypercontractility, impaired relaxation, and cardiac arrhythmias. Despite extensive research, the mutations impact on myosin contractile properties remains unclear partly due to discrepancies across different model systems. In this study, we used a multidisciplinary approach to explore mutational effects using two distinct heterozygous R403Q systems: a Yucatan minipig model and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). X-ray diffraction of R403Q minipig ventricular muscle demonstrated reduced order of the thick filament, suggesting destabilization of the inhibited OFF (vs. ON) state of myosin in relaxed muscle, which correlated with elevated force at submaximal calcium. Super-resolution, single-molecule fluorescence microscopy indicated elevated ATPase activity in thick filament zones lacking cardiac myosin binding protein-C (cMyBP-C). Furthermore, R403Q myofibrils exhibited slower activation and relaxation kinetics, with reduced sensitivity to ADP. Molecular dynamics simulations suggested that altered interactions at the actomyosin interface contribute to these effects, rather than changes at the nucleotide binding pocket, typically associated with ADP release. Human engineered heterozygous R403Q hiPSC-CMs exhibited reduced maximal myofibril force, slowed relaxation kinetics, and hypercontraction in engineered heart tissue constructs-consistent with HCM phenotypes observed in the heterozygous porcine model. Our results demonstrate that the R403Q mutation induces contractile dysfunction within the early stages of stem cell derived cardiomyocyte development and in juvenile minipigs, and that hypercontractility and slower contractile kinetics may result from a combination of an increased population of activated (ON) myosin heads and delayed detachment during cross-bridge cycling, respectively.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 143-160"},"PeriodicalIF":4.7,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409289","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 long non-coding RNA Snhg15 protects the heart after myocardial infarction","authors":"Mariana Shumliakivska ,&nbsp;Ariane Fischer ,&nbsp;Marion Muhly-Reinholz ,&nbsp;Vincent Elvin Leonard ,&nbsp;Tina Rasper ,&nbsp;Galip S. Aslan ,&nbsp;Yosif Manavski ,&nbsp;Julian U.G. Wagner ,&nbsp;Benjamin Meder ,&nbsp;Susanne S. Hille ,&nbsp;Oliver J. Müller ,&nbsp;Guillermo Luxán ,&nbsp;Stefanie Dimmeler","doi":"10.1016/j.yjmcc.2025.10.011","DOIUrl":"10.1016/j.yjmcc.2025.10.011","url":null,"abstract":"<div><div>Cardiomyocytes are postmitotic cells that do not proliferate in the heart. In order to maintain the structural integrity of the heart, cardiomyocyte loss due to cell death after myocardial infarction is compensated with a non-contractile fibrotic scar that compromises cardiac function. Here, we have combined heart failure transcriptomics with <em>in vitro</em> assays to determine the molecular mechanisms that govern cell death in heart failure. Our data identified the reduced gene expression of the long non-coding RNA (lncRNA) small nucleolar RNA host gene 15 (<em>Snhg15</em>) as a hallmark of ischemic and dilated heart failure. Furthermore, loss-of-function studies in HL-1-cardiomyocyte-like cells revealed that <em>Snhg15</em> depletion induces nucleolar disruption and cell death in a p53-dependent mechanism. Finally, adeno-associated virus delivery of <em>Snhg15</em> prior to a myocardial infarction partially protected cardiac function in the acute and chronic phases after myocardial infarction. In conclusion, our studies identify <em>Snhg15</em> as a regulator of cardiomyocyte cell death in the context of heart failure and suggest that delivery of the lncRNA may represent a potential therapeutic tool to reduce cardiomyocyte death.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 72-82"},"PeriodicalIF":4.7,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145401074","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":"Fibroblast metabolic reprogramming determines scar quality and sex-specific remodeling after infarction","authors":"Xinyu Nie ,&nbsp;Xingyue Feng ,&nbsp;Can Xu","doi":"10.1016/j.yjmcc.2025.10.010","DOIUrl":"10.1016/j.yjmcc.2025.10.010","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 161-162"},"PeriodicalIF":4.7,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145474494","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 gut microbiotasu-derived butyrate for Ferroptosis inhibition in Sepsis-induced myocardial dysfunction","authors":"Jianfei Xiong ,&nbsp;Guoxiang Liu ,&nbsp;Tianyuan Jia ,&nbsp;Qian Yang ,&nbsp;Changqing Zhu ,&nbsp;Shiwei Wang","doi":"10.1016/j.yjmcc.2025.10.005","DOIUrl":"10.1016/j.yjmcc.2025.10.005","url":null,"abstract":"<div><h3>Background</h3><div>Sepsis-induced myocardial dysfunction (SIMD) is a critical complication of sepsis, and ferroptosis has been identified as a key contributor to its pathogenesis. Emerging evidence suggests that sepsis profoundly disrupts the gut microbiota composition, leading to dysbiosis. Butyrate, a short-chain fatty acid produced by gut microbiota, has been implicated in ferroptosis regulation; however, its role in SIMD remains controversial. This study aims to elucidate the protective effects of gut microbiota-derived butyrate against SIMD through ferroptosis modulation.</div></div><div><h3>Methods</h3><div>This study assessed cardiac function using echocardiography and quantified myocardial injury biomarkers via ELISA. Myocardial iron deposition was evaluated using Prussian blue staining. The gut microbiota composition was analyzed using 16S rRNA gene sequencing. Ferroptosis-related protein expression in SIMD heart tissues and H9C2 cardiomyocytes was examined via western blotting to determine the regulatory role of butyrate.</div></div><div><h3>Results</h3><div>Sepsis-induced gut microbiota dysbiosis was characterized by a significant reduction in butyrate-producing bacteria. Echocardiographic assessments (CO, EF), myocardial injury markers (BNP, cTnI), histopathological analysis (H&amp;E staining), and cardiomyocyte ultrastructure (TEM) demonstrated that butyrate administration significantly alleviated myocardial injury in SIMD. Mechanistically, butyrate mitigated oxidative stress by increasing GSH levels and reducing MDA levels. Furthermore, butyrate treatment reversed the sepsis-induced downregulation of GPX4 and suppressed the upregulation of ACSL4 and PTGS2, thereby inhibiting ferroptosis.</div></div><div><h3>Conclusion</h3><div>These findings highlight the protective role of butyrate in SIMD, with ferroptosis inhibition serving as a key cardioprotective mechanism. Targeting gut microbiota-derived butyrate may represent a promising therapeutic strategy for sepsis-induced myocardial injury.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 119-127"},"PeriodicalIF":4.7,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370262","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}