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It commonly involves metabolic conditions such as type 2 diabetes and obesity and is associated with substantial morbidity and mortality Recently, stress\u2010induced hormone\u2010like cytokines, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), are emerging as the central two\u2010controllers of the pathophysiological network of CKM. This review is a systemic summary of the biological functions and mechanism of interaction between FGF21 and GDF15 in CKM with a focus on the functions of these two hormones in regulating energy metabolism, insulin sensitivity, inflammation, fibrosis, and cardiovascular protection. We examine their clinical relevance as disease biomarkers and discuss their prospective potential as newer therapeutic targets, in addition to discussing the obstacles that are still in the way of our translations of these findings into therapeutic application. This article will elucidate shared and distinct actions of FGF21 and GDF15 and thereby offer a thorough comprehension of integrative endocrine signaling axis output, as well as its implication to further the development of CKM management.<\/jats:p>","DOI":"10.1002\/jcb.70113","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:39:26Z","timestamp":1785242366000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel Endocrine Signaling Axis in Cardiovascular\u2010Kidney\u2010Metabolic Syndrome: Interactions and Therapeutic Potential of FGF21 and GDF15"],"prefix":"10.1002","volume":"127","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9468-2926","authenticated-orcid":false,"given":"Changlong","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Cardiology Affiliated Hospital of Zunyi Medical University Zunyi Guizhou P.R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiafei","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Affiliated Hospital of Zunyi Medical University Zunyi Guizhou P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Affiliated Hospital of Zunyi Medical University Zunyi Guizhou P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology The Second Affiliated Hospital of The Chinese University of Hong Kong Shenzhen Guangdong P.R. 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