{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T06:02:32Z","timestamp":1785391352287,"version":"3.55.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Acute myocardial infarction (AMI) triggers metabolic reprogramming, resulting in substantial lactate accumulation. This metabolite drives protein lactylation, a recently recognized post-translational modification that modulates cellular functions. However, the regulatory framework and primary drivers of lactylation in AMI, as well as their impact on myocardial repair, remain poorly defined. The hostile post-infarction microenvironment further limits the therapeutic efficacy of regenerative cell therapies, such as human endometrial mesenchymal stem cells (hEnMSCs). This study aimed to identify a central regulator of protein lactylation during AMI and develop a strategy for microenvironmental reprogramming to enhance stem cell-based interventions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Transcriptomic profiles from AMI patients were integrated with machine learning algorithms and single-cell RNA sequencing to identify core genes. Biological significance was validated using oxygen-glucose deprivation (OGD) cellular models and murine infarction paradigms, employing genetic silencing and lactate administration. The cooperative benefit of modulating the identified target in conjunction with hEnMSC delivery was subsequently assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our findings establish fibronectin 1 (FN1) as a functional bridge linking metabolic stress to epigenetic modification in AMI. Specifically, we discover that FN1 acts as a critical upstream regulator of global protein lactylation, a mechanism not previously recognized. Simultaneously, we acknowledge that FN1\u2019s well-characterized roles in fibrosis, extracellular matrix remodeling, and scar formation may operate as a parallel, independent mechanism contributing to cardiac pathology. By showing that FN1 reduction specifically attenuates lactylation and that lactate supplementation reverses the protective effect, our data pinpoint lactylation as a key downstream effector of FN1\u2019s detrimental function in AMI, while its classical functions likely remain active. Targeting this FN1-lactylation axis, particularly through combinatorial FN1 knockdown and stem cell therapy, offers a novel therapeutic strategy beyond conventional anti-fibrotic approaches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This work identifies FN1 as a critical upstream mediator of protein lactylation in AMI. Targeting FN1 not only directly attenuates tissue damage but also reshapes the local microenvironment to empower hEnMSC-mediated repair, offering a theoretical rationale for future preclinical studies combining FN1 targeting with stem cell therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1897810","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T05:41:15Z","timestamp":1785390075000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["FN1 governs global protein lactylation in acute myocardial infarction: a metabolic\u2013epigenetic axis driving cardiac injury and impeding stem cell repair"],"prefix":"10.3389","volume":"14","author":[{"given":"Jia","family":"Ren","sequence":"first","affiliation":[{"name":"The First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, Shanxi, China"]},{"name":"Department of Cardiology, The First Hospital of Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linai","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The People\u2019s Hospital of Taiyuan","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Hospital of Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Hospital of Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyue","family":"Wang","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, Shanxi, China"]},{"name":"Department of Cardiology, The First Hospital of Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gangfei","family":"Han","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, Shanxi, China"]},{"name":"Department of Cardiology, The First Hospital of Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghua","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Hospital of Shanxi Medical University","place":["Taiyuan, Shanxi, China"]},{"name":"Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education","place":["Taiyuan, Shanxi, China"]},{"name":"Shanxi Innovation Center for Integrated Management of Hypertension, Hyperlipidemia and Hyperglycemia Correlated with Cardiovascular and Cerebrovascular Diseases","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-024-08085-6","article-title":"Chromatin remodelling drives immune cell-fibroblast communication in heart failure","volume":"635","author":"Alexanian","year":"2024","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.cancergen.2021.10.008","article-title":"Integrative analysis of DNA methylation and gene expression profiles to identify biomarkers of glioblastoma","author":"Alivand","year":"2021","journal-title":"Cancer Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/s41586-024-08008-5","article-title":"Targeting immune-fibroblast cell communication in heart failure","volume":"635","author":"Amrute","year":"2024","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e808","DOI":"10.1016\/S2214-109X(25)00013-0","article-title":"Co-occurrence patterns and related risk factors of ischaemic heart disease and ischaemic stroke across 203 countries and territories: a spatial correspondence and systematic analysis","volume":"13","author":"An","year":"2025","journal-title":"Lancet Glob. 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