Role of FGF21 in Heart Failure: Molecular Insights and Therapeutic Implications

Fibroblast growth factor 21 (FGF21) has emerged as a key metabolic hormone with cardioprotective roles in heart failure (HF). It is produced by the liver, adipose tissue, and cardiomyocytes and acts through fibroblast growth factor receptor 1/β-Klotho to regulate glucose uptake, fatty acid oxidation, mitochondrial function, and adaptive stress responses. Experimental models show that FGF21 protects against pressure overload, ischemia-reperfusion injury, doxorubicin cardiotoxicity, and diabetic cardiomyopathy by enhancing oxidative metabolism and autophagy, suppressing inflammation, boosting antioxidant defenses, and reducing fibrosis. In humans, circulating FGF21 levels are elevated across HF phenotypes and correlate with N-terminal pro-B-type natriuretic peptide, inflammatory cytokines, adverse remodeling, and poor prognosis, suggesting compensatory upregulation in the context of "FGF21 resistance." Long-acting FGF21 analogs developed for metabolic diseases, such as pegozafermin and efruxifermin, improve triglycerides, insulin sensitivity, and ectopic fat, highlighting potential cardiovascular benefit. Despite these advances, several uncertainties remain. It is unclear whether FGF21 primarily reflects a biomarker of stress or actively modifies disease progression in humans. The relative importance of direct cardiac signaling versus systemic pathways remains unresolved, as does the role of receptor isoform specificity, particularly FGFR4-mediated hypertrophy seen in diabetic settings. Reference ranges and standardized assays are lacking, and long-term safety concerns such as bone loss or cachexia need further study. This review integrates molecular, preclinical, and clinical evidence to position FGF21 as both a marker and a therapeutic target in HF. It aims to focus on mechanisms of action, evaluate its prognostic value, assess therapeutic analogs, and outline future directions for translating FGF21 into metabolism-focused strategies for HF management.