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Cardiovasc. Med."],"abstract":"<jats:p>Cardiovascular\u2013kidney\u2013metabolic (CKM) syndrome represents a pathophysiological continuum linking metabolic dysfunction, chronic kidney disease (CKD), and cardiovascular disease (CVD) through shared mechanisms, including insulin resistance, chronic inflammation, endothelial dysfunction, mitochondrial impairment, and maladaptive interorgan crosstalk. Although exerkines have emerged as key mediators of exercise-induced benefits, an integrated exerkine-centered framework spanning the CKM spectrum remains lacking. This review synthesizes current evidence on the multiorgan origins and biological roles of major exerkines, including myokines, adipokines, hepatokines, cardiokines, osteokines, lipid mediators, and extracellular vesicle\u2013associated cargos. Moreover, extending beyond reductionist descriptions, we propose a higher-level mechanistic synthesis in which exerkines function as coordinated \u201csignatures\u201d across CKM phenotypes, converging on key regulatory hubs, particularly AMP-activated protein kinase (AMPK)\u2013peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1\u03b1)-mediated metabolic adaptation and the Klotho\/fibroblast growth factor (FGF) axis that links renal, metabolic, and cardiovascular regulation. From a translational perspective, adiponectin, FGF21, apelin, and Klotho demonstrate the most consistent associations with cardiometabolic and renal outcomes in humans. However, clinical application remains constrained by uncertain causality, context-dependent resistance, and variability in assay performance. Overall, exerkines are best conceptualized as components of an integrated signaling network rather than isolated therapeutic targets. Meanwhile, future progress will depend on defining disease-stage-specific exerkine signatures and establishing associated causal relevance in humans.<\/jats:p>","DOI":"10.31083\/rcm50762","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:57:11Z","timestamp":1790693831000},"source":"Crossref","is-referenced-by-count":0,"title":["Exerkines in Cardiovascular\u2013Kidney\u2013Metabolic Syndrome: An Integrative Framework for Mechanisms and Therapeutic Implications\u2014A Narrative Review"],"prefix":"10.31083","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0656-1606","authenticated-orcid":true,"given":"Hongyan","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Jiaxing University, 314001 Jiaxing, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0593-6102","authenticated-orcid":true,"given":"Changlin","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Jiaxing University, 314001 Jiaxing, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6183-6571","authenticated-orcid":true,"given":"Chaojie","family":"He","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Jiaxing University, 314001 Jiaxing, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9855-8325","authenticated-orcid":true,"given":"Liang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Jiaxing University, 314001 Jiaxing, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7118-7866","authenticated-orcid":true,"given":"Haihua","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Jiaxing University, 314001 Jiaxing, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7271-1684","authenticated-orcid":true,"given":"Wenwen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The Second Affiliated Hospital of Jiaxing University, 314001 Jiaxing, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, Tuttle KR, Khan SS, et al. 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