VPS37A is a critical component of the ESCRT-I complex that regulates vesicular trafficking and autophagosome completion. The protein directs ESCRT machinery recruitment for phagophore closure during autophagy, with its N-terminal putative ubiquitin E2 variant domain being essential for this function 1. VPS37A coordinates the recruitment of VPS28 and CHMP2A to phagophores, facilitating proper autophagosome formation 1. Beyond autophagy regulation, VPS37A controls cellular signaling pathways by promoting degradation of key receptors. It regulates hepatic glucose production by controlling glucagon receptor localization to endosomes, uncoupling glucose production from lipid metabolism 2. Additionally, VPS37A promotes STING degradation through ESCRT-dependent mechanisms, thereby terminating STING-mediated innate immune signaling 3. In colorectal cancer, VPS37A acts as a tumor suppressor by directing TNFR1 to lysosomal degradation, which suppresses NF-κB signaling and promotes stress-induced cell death 4. VPS37A deficiency is associated with spastic paraplegia 53, an autosomal recessive disorder characterized by progressive lower extremity weakness and spasticity 5. The protein's loss creates therapeutic vulnerabilities in cancer cells by disrupting basal autophagy and sensitizing cells to autophagy inhibitors 6.