<i>ZNF460</i> knockdown reduced pyroptotic cell death and preserved aortic wall integrity <i>in vivo</i>.<h4>Conclusions</h4>This study identifies ZNF460 as a novel upstream regulator of <i>PKM2</i> that drives GSDME-dependent pyroptosis, thereby exacerbating AD progression. Here, GSDME is linked to Alzheimer disease.