Exerkines in Cardiovascular–Kidney–Metabolic Syndrome: An Integrative Framework for Mechanisms and Therapeutic Implications—A Narrative Review

Cardiovascular–kidney–metabolic (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–associated cargos. Moreover, extending beyond reductionist descriptions, we propose a higher-level mechanistic synthesis in which exerkines function as coordinated “signatures” across CKM phenotypes, converging on key regulatory hubs, particularly AMP-activated protein kinase (AMPK)–peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-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.