{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T14:59:45Z","timestamp":1792162785734,"version":"4.4.0"},"reference-count":120,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32171130"],"award-info":[{"award-number":["32171130"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic diseases, including cardiovascular diseases, type 2 diabetes mellitus (T2DM), osteoporosis, and non-alcoholic fatty liver disease (NAFLD), constitute a major global health burden associated with chronic morbidity and mortality. Lactate, once considered as a metabolic byproduct, has emerged as a key regulator of cellular reprogramming through lactylation, a novel post-translational modification (PTM) that dynamically couples metabolic flux to chromatin remodeling. Lactylation exerts dual regulatory roles as a signaling molecule via GPR81\/GPR4-mediated pathways and as a substrate for the covalent modification of histones and metabolic enzymes. Pathologically, chronic hyperlactatemia suppresses mitochondrial biogenesis, driving metabolic cardiomyopathy through the epigenetic silencing of oxidative metabolism genes. Conversely, exercise-induced lactate surges transiently enhance insulin sensitivity via AMPK\/PGC-1\u03b1\/GLUT4 signaling, resolve inflammation through GPR81-mediated M2 macrophage polarization, and restore mitochondrial function via lactylation-dependent pathways. This review delineates lactylation as a spatiotemporal rheostat: chronic dysregulation perpetuates metabolic disorders, whereas acute exercise-mediated lactylation remodels transcriptional networks to restore metabolic homeostasis. Future research should integrate multiomics to clarify lactylation\u2019s spatiotemporal dynamics, tissue-specific thresholds, metabolism\u2013immunity interactions, and metabolic\u2013epigenetic crosstalk for the precision management of metabolic diseases.<\/jats:p>","DOI":"10.3390\/ijms26083469","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T11:05:02Z","timestamp":1744110302000},"page":"3469","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Mechanisms for Regulatory Effects of Exercise on Metabolic Diseases from the Lactate\u2013Lactylation Perspective"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6497-1947","authenticated-orcid":false,"given":"Guannan","family":"Chen","sequence":"first","affiliation":[{"name":"College of Physical Education and Health, East China Normal University, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinchao","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Physical Education and Health, East China Normal University, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilan","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Physical Education and Health, East China Normal University, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0615-2510","authenticated-orcid":false,"given":"Peng","family":"Sun","sequence":"additional","affiliation":[{"name":"College of Physical Education and Health, East China Normal University, Shanghai 200241, China"},{"name":"The Key Laboratory of Adolescent Health Assessment and Exercise Intervention of the Ministry of Education, East China Normal University, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","article-title":"Global Burden of Cardiovascular Diseases and Risk Factors, 1990\u20132019","volume":"76","author":"Roth","year":"2020","journal-title":"J. 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