Emerging Myostatin and Metabolic Hormone Pathway Modulators in Cardiometabolic Disease: Mechanisms, Evidence, and Therapeutic Potential.

Cardiometabolic disease comprises obesity, type 2 diabetes, heart failure, and sarcopenic obesity, which share interconnected mechanisms including muscle wasting, metabolic dysfunction, fibrosis, mitochondrial impairment, and chronic inflammation. Current therapies primarily target individual risk factors rather than these shared pathways. This review summarizes mechanistic and translational evidence on three emerging pathway modulators-myostatin (MSTN), fibroblast growth factor 21 (FGF21), and growth differentiation factor 15 (GDF15)-and their integration with incretin biology, AMPK/mTOR signaling, fibrosis, and metabolic regulation. Myostatin inhibition increases lean body mass but has shown inconsistent functional benefits. FGF21 analogs improve insulin sensitivity, lipid metabolism, hepatic steatosis, and cardiac energetics. GDF15 functions as both a biomarker and therapeutic target for metabolic stress and cachexia, while GLP-1/GIP therapies favorably influence inflammation, fibrosis, and substrate utilization. Coordinated modulation of these pathways, supported by precision phenotyping and biomarker-guided monitoring, offers a promising strategy for comprehensive cardiometabolic remodeling.