PACS2 is a multifunctional sorting protein that serves as a critical regulator of mitochondria-associated endoplasmic reticulum membranes (MAMs), dynamic coupling regions between the mitochondrial outer membrane and ER 1. Its primary function involves controlling ER-mitochondria communication, maintaining ER homeostasis, and regulating mitochondrial dynamics and mitophagy 2. PACS2 facilitates MAM formation by tethering mitochondria to the ER and mediates mitophagy by binding to BECN1 and promoting its relocalization to MAM sites to facilitate mitophagosome formation 3. Mechanistically, PACS2 regulates calcium signaling and lipid metabolism at MAMs while preventing excessive mitochondrial fission by blocking DRP1 recruitment 3. Under ER stress, PACS2 levels are modulated by TRPV1 interaction, and PACS2-TRPV1 axis restoration protects against epithelial apoptosis 4. PACS2 also initiates foam cell formation through ROS-PPARγ-CD36 signaling, creating a positive feedback loop that drives atherosclerosis progression 5. Clinically, PACS2 dysfunction causes early infantile epileptic encephalopathy (EIEE66), characterized by seizures within the first week of life, cerebellar hypoplasia, and developmental delay 6. Decreased PACS2 expression contributes to diabetic kidney disease pathogenesis through MAM disruption and mitochondrial fragmentation via MAPK1-dependent mechanisms 7, 3. PACS2 represents a therapeutic target in neurodegenerative diseases, obesity-related disorders, and diabetic complications 2.