USP5 Stabilizes TGFBR1 to Drive Vascular Smooth Muscle Cell Senescence and Atherosclerosis

Vascular smooth muscle cell (VSMC) senescence contributes importantly to atherosclerotic plaque progression, yet the upstream mechanisms remain incompletely understood. Here, by integrating single-cell RNA sequencing analysis with human plaque validation, we found that TGFBR1 is enriched in senescent VSMCs in atherosclerotic lesions and correlates with senescence-associated markers. In vivo, VSMC-specific TGFBR1 knockin in Apoe-deficient mice accelerated plaque development and increased VSMC senescence. Mechanistically, we identified the deubiquitinase USP5 as a previously unrecognized stabilizer of TGFBR1. USP5 directly interacted with TGFBR1 and selectively removed K48-linked polyubiquitin chains at lysine 213, thereby preventing proteasomal degradation. Stabilized TGFBR1 suppressed the mitochondrial enzyme IDH2, driving a metabolic shift toward glycolysis that sustained apoptosis resistance in senescent VSMCs. Conversely, VSMC-specific knockdown of USP5 reduced TGFBR1 expression, restored IDH2 expression, attenuated glycolytic remodeling, and mitigated atherosclerosis in vivo. Our findings reveal a USP5-TGFBR1-IDH2 axis in which site-specific deubiquitination at K213 links receptor stability to metabolic remodeling and VSMC senescence, identifying USP5 as a potential therapeutic target for atherosclerosis.