ZNF460 Promotes GSDME-Driven Pyroptosis via PKM2 Transcriptional Activation in Aortic Dissection

Aortic dissection (AD) is a cardiovascular emergency with high mortality; however, the underlying molecular pathophysiology of AD remains incompletely understood. Pyroptosis, a proinflammatory form of programmed cell death, contributes to vascular injury; nonetheless, the upstream transcriptional regulation of pyroptosis in AD is similarly poorly defined.

Differentially expressed genes were identified in aortic tissues from AD patients (Gene Expression Omnibus (GEO) datasets) using bioinformatics analyses, with a focus on cell death-related candidates. In vivo AD mouse models and in vitro vascular smooth muscle cell (VSMC) systems were employed to investigate the roles of these genes in AD. Potential transcription factors for pyruvate kinase M2 (PKM2) were predicted using the Just Another Simple Array Retrieval/Simple API for Repository (JASPAR) and University of California, Santa Cruz (UCSC) databases, and validated by luciferase reporter and chromatin immunoprecipitation assays. Gain- and loss-of-function approaches were used to dissect the zinc finger protein 460 (ZNF460)-PKM2-gasdermin E (GSDME) axis and the associated impact on pyroptosis and AD progression.

PKM2 expression was markedly elevated in AD tissues. PKM2 silencing suppressed GSDME cleavage, attenuated VSMC pyroptosis, and mitigated experimental AD, whereas PKM2 overexpression aggravated these outcomes. GSDME upregulation rescued pyroptosis in PKM2-depleted cells. Mechanistically, the transcription factor ZNF460 directly bound to the PKM2 promoter, enhancing PKM2 transcription and activating downstream GSDME-mediated pyroptosis. ZNF460 knockdown reduced pyroptotic cell death and preserved aortic wall integrity in vivo.

This study identifies ZNF460 as a novel upstream regulator of PKM2 that drives GSDME-dependent pyroptosis, thereby exacerbating AD progression. Targeting the ZNF460-PKM2-GSDME axis may represent a promising therapeutic strategy for preventing pyroptosis-driven vascular damage in AD.