Our results implied that SAA could ameliorate atherosclerosis in Western diet-fed STZ-induced diabetic ApoE−/− mice by regulating endothelial pyroptosis via the PKM2/PKR/NLRP3 inflammasome signaling pathway, demonstrating the potential use of SAA as a therapy to relieve diabetes mellitus and its related macrovascular complications. Here, PKM is linked to atherosclerosis.