Int Immunopharmacol. 2026 Sep 12;189:117374. doi: 10.1016/j.intimp.2026.117374. Online ahead of print.
ABSTRACT
Atherosclerosis (AS) is a chronic inflammatory disease in which vascular smooth muscle cell (VSMC) pyroptosis and foam cell formation play critical roles. Curcumin has anti-atherosclerotic effects, but its molecular mechanism remains unclear. In this study, we investigated whether and how curcumin regulates VSMC pyroptosis and foam cell formation via Phospholipase C gamma 2 (PLCG2) in AS. An ApoE-/- mouse model of AS and an ox-LDL-stimulated Mouse Vascular Aortic Smooth muscle cell (MOVAS) cell model were established. Curcumin treatment significantly reduced PLCG2 protein expression without affecting its mRNA level. Mechanistically, curcumin promoted CBLC-mediated K148-linked ubiquitination and proteasomal degradation of PLCG2. PLCG2 knockdown recapitulated the protective effects of curcumin, suppressing NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation, VSMC pyroptosis, foam cell formation, and atherosclerotic plaque progression, whereas PLCG2 overexpression reversed these effects. Further studies revealed that PLCG2 contributes to the activation of the JNK/JUN signaling pathway, thereby promoting NLRP3 inflammasome-mediated pyroptosis and foam cell formation. Notably, activation of the NLRP3 inflammasome by Nigericin or activation of the JNK pathway by Anisomycin partially reversed the inhibitory effects of PLCG2 knockdown. In conclusion, curcumin alleviates AS by promoting CBLC-mediated ubiquitination and degradation of PLCG2, thereby suppressing the JNK/JUN-NLRP3 pyroptosis pathway and VSMC-derived foam cell formation. PLCG2 is identified as an important downstream mediator contributing to the anti-atherosclerotic effects of curcumin in AS.
PMID:42731465 | DOI:10.1016/j.intimp.2026.117374