Cartilage oligomeric matrix protein inhibits CKD-associated vascular calcification by suppressing PANoptosis in VSMCs via the AT1R/β-arrestin-2 axis.

Vascular calcification (VC), a common complication of chronic kidney disease (CKD), substantially contributes to cardiovascular morbidity. Although distinct forms of programmed cell death have been implicated in VC, the role of PANoptosis remains unclear. This study investigated the involvement of PANoptosis in CKD-associated VC and explored its regulatory mechanisms. Transcriptomic analysis of the GSE146638 dataset combined with machine learning algorithms was used to identify key PANoptosis-related genes associated with VC. CKD-associated VC was established in adenine/high-phosphate-fed mice and 5/6-nephrectomized rats fed a high-phosphate diet. In vitro, vascular smooth muscle cells (VSMCs) transfected with cartilage oligomeric matrix protein (COMP) small interfering RNA (siRNA) were subsequently stimulated with β-glycerophosphate (β-GP), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) to induce calcification-associated PANoptosis. Protein interactions and downstream signaling pathways were explored using co-immunoprecipitation (Co-IP). CKD-associated VC was characterized by concurrent activation of apoptosis, pyroptosis, and necroptosis in VSMCs, indicating PANoptosis activation in vivo and in vitro. Through an integrative bioinformatics strategy, COMP was identified as a hub gene exhibiting markedly reduced expression in calcified vessels. COMP deficiency aggravated VSMC calcification and enhanced PANoptotic signaling. Mechanistically, COMP directly interacted with angiotensin II type 1 receptor (AT1R) and restrained β-arrestin-2-dependent signaling, thereby limiting PANoptosome assembly. Conversely, COMP depletion promoted PANoptosis and calcification, whereas β-arrestin-2 inhibition largely reversed these effects. Collectively, these findings demonstrate that PANoptosis contributes to CKD-associated VC. COMP protects against VC by restraining AT1R-dependent β-arrestin-2 signaling, thereby suppressing PANoptosis, identifying the COMP-AT1R-β-arrestin-2 axis as a potential therapeutic target for cardiovascular complications in CKD.