Abstract / Summary
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide, necessitating novel biomarkers and therapeutic targets. Irisin, a myokine derived from FNDC5, has emerged as a molecule of interest owing to its pleiotropic effects, yet its role in cardiovascular health is debated amid conflicting clinical findings and severe measurement challenges. This review synthesizes and critically evaluates the evidence on irisin in ASCVD, examining its molecular mechanisms, potential as a clinical biomarker, and hurdles for therapeutic application. Preclinical evidence has demonstrated that irisin exerts multifaceted cardioprotective effects: it mitigates cellular stress by enhancing mitochondrial quality control and inhibiting apoptosis and pyroptosis; preserves vascular integrity by promoting angiogenesis and preventing pathological remodeling; and enhances the efficacy of regenerative stem cell therapies. Most clinical studies have revealed an inverse correlation between circulating irisin levels and the presence and severity of ASCVD, heart failure, and related inflammatory conditions. However, these studies are predominantly observational and often cross-sectional, frequently with small sample sizes, and paradoxical elevations occur in certain metabolic states and during acute cardiac injury. Critically, the field is hampered by profound measurement inconsistencies, with reported values spanning picograms to micrograms per millilitre, making cross-study comparisons and clinical cutoffs currently impossible. Irisin appears to be an important endogenous factor in cardiovascular health, and preclinical evidence suggests that it is a promising candidate therapeutic target; however, clinical validation is lacking. Standardization of irisin assays remains the critical step required to determine whether irisin can become a reliable clinical biomarker.