VPS37A Activates the Autophagy-Lysosomal Pathway for TNFR1 Degradation and Induces NF-

Background: VPS37A (VPS37A subunit of ESCRT-I), a component of the ESCRT-I (endosomal sorting complex required for transport I) complex, mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into multivesicular bodies (MVBs). Although accumulating evidence indicates that VPS37A deficiency occurs in numerous malignancies and exerts tumor-suppressive effects during cancer progression, its functional significance in colorectal cancer (CRC) pathogenesis remains poorly characterized. Therefore, this study aims to further investigate the functional and molecular mechanisms by which VPS37A downregulation contributes to malignant biological phenotypes in CRC, with a specific focus on how its dysregulation affects cell death pathways. Methods: Multi-omics analysis of TCGA, GEO, and CPTAC cohorts identified VPS37A as a downregulated tumor suppressor gene in CRC. The prognostic relevance of VPS37A was validated in two clinical cohorts (Cohorts 1 and 2) using immunohistochemistry. Functional assays in VPS37A-overexpressing CRC cells and xenografts assessed proliferation, cell cycle progression, and stress-induced cell death. RNA sequencing, nuclear factor kappa-B (NF-κB) luciferase reporter assays, and lysosomal inhibition experiments elucidated the mechanisms underlying tumor necrosis factor receptor 1 (TNFR1) degradation. Results: VPS37A is significantly downregulated in advanced-stage CRC and independently predicts poor survival. Functionally, VPS37A overexpression suppresses proliferation and induces G2/M arrest Conclusion: VPS37A deficiency drives CRC progression by sustaining TNFR1/NF-κB signaling under metabolic stress. Restoring VPS37A activity promotes TNFR1 degradation, offering a therapeutic strategy to counteract NF-κB-mediated treatment resistance in CRC.