{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:33:44Z","timestamp":1792794824058,"version":"4.5.0"},"reference-count":209,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Metabolic syndrome (MetS) is a clinical condition defined by the coexistence of interconnected cardiometabolic risk factors, including central obesity, dyslipidemia, elevated blood pressure, and impaired glucose regulation, which collectively increase the risk of type 2 diabetes mellitus and cardiovascular disease. Beyond these clinical diagnostic features, MetS is characterized by complex pathophysiological alterations involving systemic dysregulation of metabolic signaling across adipose tissue, skeletal muscle, liver, vascular endothelium, and the immune system. Key molecular alterations include impaired insulin receptor substrate (IRS)\u2013Akt signaling, chronic nuclear factor kappa B (NF-\u03baB) activation, mitochondrial dysfunction, and oxidative stress. Physical exercise is recognized as a pleiotropic biomedical intervention capable of restoring metabolic homeostasis through coordinated modulation of intracellular signaling pathways and inter-organ communication. Exercise activates AMP-activated protein kinase (AMPK), enhances peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1\u03b1)-mediated mitochondrial biogenesis, and stimulates nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant responses. These adaptations improve glucose uptake, enhance fatty acid oxidation, and reduce ectopic lipid accumulation across metabolically active tissues. At the systemic level, skeletal muscle functions as an endocrine organ by releasing myokines such as irisin, interleukin-6 (IL-6), and fibroblast growth factor 21 (FGF21), which contribute to metabolic regulation across the liver, adipose tissue, and vasculature. These exercise-induced signals promote immune modulation, reduce pro-inflammatory cytokine production, and improve endothelial function. Different exercise modalities including aerobic, resistance, and high-intensity interval training (HIIT) activate both common and modality-specific molecular pathways, supporting individualized exercise strategies. Collectively, exercise targets the multi-organ pathophysiology of MetS and provides a mechanistic foundation for precision exercise medicine in cardiometabolic disease management.<\/jats:p>","DOI":"10.3390\/cimb48080850","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T09:31:59Z","timestamp":1787304719000},"page":"850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exercise as a Molecular Therapeutic Strategy in Metabolic Syndrome: Integrating Cellular Signaling, Organ Crosstalk, and Clinical Translation\u2014A Narrative Review"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0774-0848","authenticated-orcid":false,"given":"H\u00e9ctor","family":"Fuentes-Barr\u00eda","sequence":"first","affiliation":[{"name":"Centro de Investigaci\u00f3n en Medicina de Altura (CEIMA), Universidad Arturo Prat, Iquique 1110939, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4123-4255","authenticated-orcid":false,"given":"Ra\u00fal","family":"Aguilera-Egu\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Salud P\u00fablica, Facultad de Medicina, Universidad Cat\u00f3lica de la Sant\u00edsima Concepci\u00f3n, Concepci\u00f3n 3349001, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Alarc\u00f3n-Rivera","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n, Universidad Bernardo O\u2019Higgins, Santiago 8370993, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5294-7157","authenticated-orcid":false,"given":"Cherie","family":"Flores-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Departamento de Gesti\u00f3n de la Informaci\u00f3n, Universidad Tecnol\u00f3gica Metropolitana, Santiago 7550000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-031-63657-8_1","article-title":"The Definition and Prevalence of Obesity and Metabolic Syndrome: Correlative Clinical Evaluation Based on Phenotypes","volume":"Volume 1460","author":"Engin","year":"2024","journal-title":"Obesity and Lipotoxicity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s40256-025-00761-w","article-title":"Definition, Classification, Diagnosis, and Management of an Emerging Threat: Cardio-Renal-Metabolic Syndrome","volume":"26","author":"Koufakis","year":"2026","journal-title":"Am. 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