PPARα: Linking Cardiac Metabolism to Therapeutic Opportunities in Cardiovascular Diseases

Peroxisome proliferator-activated receptor alpha (PPARα) is a key transcriptional regulator of lipid metabolism, highly expressed in metabolically active organs such as the heart. In cardiomyocytes, where approximately 70% of energy is derived from fatty acid oxidation, PPARα plays a central role in maintaining metabolic homeostasis. Moreover, the transcription factor is implicated in postnatal maturation of the heart and immune modulation. Dysregulation of PPARα signaling has profound consequences for cardiac energy balance, particularly under stress conditions. Accordingly, its role has been extensively investigated in cardiovascular diseases, including ischemia/reperfusion, diabetic cardiomyopathy and sepsis-induced cardiomyopathy. Upon ischemia/reperfusion and sepsis, cardiac PPARα expression is typically downregulated, contributing to impaired fatty acid breakdown and reduced metabolic flexibility. In contrast, diabetic cardiomyopathy is characterized by sustained PPARα activation, promoting excessive fatty acid oxidation, lipid accumulation and lipotoxicity. These context-dependent effects highlight a complex role of PPARα in cardiac diseases. PPARα has emerged as a promising therapeutic target, as its modulation can alleviate cardiac injury in preclinical models. However, further research is required to validate its efficacy in human disease, improve cardiomyocyte-specific targeting strategies to minimize systemic side effects, and better define optimal timing of intervention, as inappropriate or prolonged modulation may lead to detrimental outcomes.