VPS37C is a component of the ESCRT-I complex that plays a crucial role in endosomal sorting and viral budding processes 1. The protein forms a ternary complex with Tsg101 and VPS28, binding to the carboxyl terminus of Tsg101 and interacting with the class E VPS factor Hrs 1. VPS37C is essential for ESCRT-I-dependent viral budding, as demonstrated by its recruitment to the plasma membrane by HIV-1 Gag and its ability to obviate the requirement for PTAP motifs when directly fused to viral Gag proteins 1. The protein is subject to regulatory phosphorylation by TANK-binding kinase 1 (TBK1), which attenuates PTAP-dependent retroviral budding as a host defense mechanism independent of interferon signaling 2. VPS37C shows non-redundant functions compared to other VPS37 proteins, and its concurrent depletion with VPS37A/B triggers ESCRT-I destabilization, leading to p21-mediated cell cycle arrest and NF-κB-driven inflammatory responses 3. Clinically, VPS37C expression alterations have been associated with various conditions including abdominal aortic aneurysms 4, multisystem inflammatory syndrome in children 5, long COVID in males 6, and acute myeloid leukemia prognosis 7, indicating its broader physiological significance beyond endosomal sorting.