{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T12:27:59Z","timestamp":1784636879919,"version":"3.55.0"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the talent Program of Fushun City of China","award":["FSYC202107012"],"award-info":[{"award-number":["FSYC202107012"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Heart failure (HF) is a global health challenge with high morbidity and mortality. While dapagliflozin (DAPA), a sodium\u2013glucose cotransporter 2 inhibitor, has proven clinical benefits in HF, its molecular mechanisms remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated bulk and single-cell transcriptomic analyses with experimental validation to investigate the role of STAT1 in HF and its modulation by DAPA. Bulk RNA sequencing data from the GSE57345 dataset were analyzed for differential expression, enrichment, and weighted gene co-expression network analysis (WGCNA) to identify hub regulators. Single-cell RNA sequencing data (GSE145154) included normal controls (n\u2009=\u20094), dilated cardiomyopathy (DCM, n\u2009=\u20098), ischemic cardiomyopathy infarct regions (ICM_MI, n\u2009=\u20096), and non-infarct regions (ICM_NMI, n\u2009=\u20096), and were processed with Seurat and Harmony for integration, clustering, myeloid subcluster profiling, and AUCell pathway scoring. For in vivo validation, a rat model of myocardial infarction\u2013induced HF was established and divided into control, HF, and HF+DAPA groups (6 mg\/kg\/day for 4 weeks). Histological examination, Western blotting, ELISA, flow cytometry, and serum bile acid assays were conducted. For in vitro assays, STAT1-overexpressing H9C2 cardiomyocytes were generated by lentiviral transduction. Cell viability (CCK\u20118), STAT1 expression (qPCR and Western blot), and apoptosis (Annexin V\/PI flow cytometry) were assessed with or without DAPA treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Transcriptomic analyses revealed widespread activation of bile acid, amino acid, and lipoic acid metabolic pathways in HF, coupled with immune remodeling dominated by increased M1 and reduced M2 macrophages. STAT1 emerged as a central hub gene linking metabolic stress and immune imbalance. Single-cell analysis confirmed aberrant STAT1 expression particularly in M1 and proliferating myeloid clusters. In vivo, DAPA suppressed myocardial STAT1 expression, alleviated inflammation, normalized macrophage polarization, and reduced cytokine and bile acid abnormalities. In vitro, DAPA rescued STAT1-overexpressing cardiomyocytes by restoring viability and reducing apoptosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>STAT1 acts as a pivotal mediator bridging metabolic disturbances and immune dysregulation in HF. DAPA alleviates HF by inhibiting STAT1 signaling, thereby restoring immunometabolic balance and protecting cardiac tissue. These findings provide mechanistic insight into the cardioprotective effects of DAPA and position STAT1 as a promising biomarker and potential therapeutic candidate for HF management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0343296","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T18:40:01Z","timestamp":1772217601000},"page":"e0343296","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dapagliflozin mitigates myocardial inflammation and metabolic stress in heart failure through STAT1 inhibition: Evidence from multi-omics analyses and experimental exploration"],"prefix":"10.1371","volume":"21","author":[{"given":"Lianqi","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichao","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihong","family":"Huangfu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiran","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4428-4014","authenticated-orcid":true,"given":"Zhanchun","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"issue":"8","key":"pone.0343296.ref001","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1053\/euhj.2000.2493","article-title":"The heart failure epidemic: exactly how big is it?","volume":"22","author":"JGF Cleland","year":"2001","journal-title":"European Heart Journal"},{"key":"pone.0343296.ref002","doi-asserted-by":"crossref","first-page":"17058","DOI":"10.1038\/nrdp.2017.58","article-title":"Heart failure with reduced ejection fraction","volume":"3","author":"MW Bloom","year":"2017","journal-title":"Nat Rev Dis Primers"},{"issue":"11","key":"pone.0343296.ref003","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1056\/NEJMoa1409077","article-title":"Angiotensin-neprilysin inhibition versus enalapril in heart failure","volume":"371","author":"JJV McMurray","year":"2014","journal-title":"N Engl J Med"},{"issue":"17","key":"pone.0343296.ref004","doi-asserted-by":"crossref","first-page":"3272","DOI":"10.1093\/cvr\/cvac013","article-title":"Global burden of heart failure: a comprehensive and updated review of epidemiology","volume":"118","author":"G Savarese","year":"2023","journal-title":"Cardiovasc Res"},{"issue":"4","key":"pone.0343296.ref005","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1161\/CIRCULATIONAHA.113.001878","article-title":"Pathological ventricular remodeling: mechanisms: part 1 of 2","volume":"128","author":"JS Burchfield","year":"2013","journal-title":"Circulation"},{"key":"pone.0343296.ref006","doi-asserted-by":"crossref","unstructured":"Marwick TH. Implications of Underlying Mechanisms for the Recognition and Management of Diabetic Cardiomyopathy. 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(Camb)"},{"issue":"1","key":"pone.0343296.ref025","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/s41556-019-0446-7","article-title":"Single-cell reconstruction of the adult human heart during heart failure and recovery reveals the cellular landscape underlying cardiac function","volume":"22","author":"L Wang","year":"2020","journal-title":"Nat Cell Biol"},{"issue":"5","key":"pone.0343296.ref026","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1161\/CIRCULATIONAHA.119.045401","article-title":"Transcriptional and cellular diversity of the human heart","volume":"142","author":"NR Tucker","year":"2020","journal-title":"Circulation"},{"issue":"15","key":"pone.0343296.ref027","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1161\/CIRCULATIONAHA.119.045115","article-title":"High-Resolution Transcriptomic Profiling of the Heart During Chronic Stress Reveals Cellular Drivers of Cardiac Fibrosis and Hypertrophy","volume":"142","author":"MA McLellan","year":"2020","journal-title":"Circulation"},{"issue":"1","key":"pone.0343296.ref028","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/s41590-018-0272-2","article-title":"Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction","volume":"20","author":"SA Dick","year":"2019","journal-title":"Nat Immunol"},{"key":"pone.0343296.ref029","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.43882","article-title":"Single-cell expression profiling reveals dynamic flux of cardiac stromal, vascular and immune cells in health and injury","volume":"8","author":"N Farbehi","year":"2019","journal-title":"Elife"},{"issue":"25","key":"pone.0343296.ref030","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1161\/CIRCULATIONAHA.119.041694","article-title":"Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload-Driven Heart Failure Reveals Extent of Immune Activation","volume":"140","author":"E Martini","year":"2019","journal-title":"Circulation"},{"issue":"28","key":"pone.0343296.ref031","doi-asserted-by":"crossref","first-page":"20059","DOI":"10.1074\/jbc.R700016200","article-title":"JAK-STAT signaling: from interferons to cytokines","volume":"282","author":"C Schindler","year":"2007","journal-title":"J Biol Chem"},{"key":"pone.0343296.ref032","article-title":"Interferome v2.0: an updated database of annotated interferon-regulated genes","volume":"41","author":"I Rusinova","year":"2013","journal-title":"Nucleic Acids Res"},{"issue":"26","key":"pone.0343296.ref033","doi-asserted-by":"crossref","first-page":"8944","DOI":"10.1073\/pnas.0801794105","article-title":"Recruitment of Stat1 to chromatin is required for interferon-induced serine phosphorylation of Stat1 transactivation domain","volume":"105","author":"I Sadzak","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"pone.0343296.ref034","article-title":"Nucleic DHX9 cooperates with STAT1 to 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Metwally","year":"2024","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"15","key":"pone.0343296.ref038","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1056\/NEJMoa2022190","article-title":"Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure","volume":"383","author":"M Packer","year":"2020","journal-title":"N Engl J Med"},{"issue":"22","key":"pone.0343296.ref039","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes","volume":"373","author":"B Zinman","year":"2015","journal-title":"N Engl J Med"},{"issue":"7","key":"pone.0343296.ref040","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1161\/CIRCRESAHA.116.302317","article-title":"Innate immunity and the failing heart: the cytokine hypothesis revisited","volume":"116","author":"DL Mann","year":"2015","journal-title":"Circ 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