The novel piperlongumine-ligustrazine derivative PL-Lig-11 inhibits VSMC phenotypic switching and intimal hyperplasia via the PDGFRα/β-RhoGDI3-NLRP3 inflammasome axis

Neointimal hyperplasia driven by vascular smooth muscle cell (VSMC) phenotypic switching is a key pathological process in cardiovascular diseases. This study investigated the effects and mechanisms of PL-Lig-11, a novel derivative combining piperlongumine (PL) and ligustrazine (Lig), on VSMC phenotypic switching and intimal hyperplasia. PL-Lig-11 significantly suppressed PDGF-BB-induced VSMC proliferation, migration, and phenotypic transformation, and attenuated intimal thickening in rat carotid arteries, showing superior efficacy to the parent compounds. Mechanistically, PL-Lig-11 reduced both the protein levels and phosphorylation of PDGFRα/β, relieved autophagic flux inhibition, and enhanced autophagic-lysosomal turnover of PDGFRα/β. Additionally, PL-Lig-11 downregulated RhoGDI3 expression-an effect not observed with PL or Lig alone-and PDGFRα/β overexpression reversed both RhoGDI3 suppression and the protective effects of PL-Lig-11 on VSMC phenotypic switching. Furthermore, PL-Lig-11 promoted K48-linked ubiquitination of NLRP3, inhibited ASC transcription, and disrupted the co-localization of RhoGDI3 with NLRP3 and ASC, as well as NLRP3-ASC assembly, which correlated with reduced Caspase-1 and IL-1β activation. These effects were reversed by RhoGDI3 overexpression. Collectively, the observed inhibition of VSMC phenotypic switching and alleviation of neointima formation by PL-Lig-11 are consistent with the involvement of the PDGFRα/β-RhoGDI3-NLRP3 inflammasome axis, positioning it as a promising candidate for treating vascular restenosis.