PACS2 at Mitochondria-Associated Membranes: A Central Regulator of Cardiovascular and Metabolic Diseases

Cardiovascular and metabolic diseases (CVMDs), which are characterized by metabolic dysregulation and cardiovascular impairment, constitute a major global cause of mortality, thus highlighting the urgent need for novel therapeutic strategies. Phosphofurin acidic cluster sorting protein 2 (PACS2), a multifunctional adapter protein localized to mitochondria-associated membranes (MAMs), regulates intracellular membrane trafficking and is pivotal for critical cellular processes, including apoptosis, autophagy and ferroptosis. Accumulating evidence implicates PACS2 dysregulation in the pathogenesis of diverse CVMDs, including metabolic disorders and cardiovascular conditions. This review examines the structural and functional basis of PACS2 and details its established and emerging roles in the pathogenesis of CVMDs. Collectively, these findings identify PACS2 as a crucial regulator of CVMD development and progression, underscoring its significant potential as both a diagnostic biomarker and a promising therapeutic target.