In the present study inhibition of GSDMD activation by a novel mouse GSDMD inhibitor, Z-LLSD-FMK, and a specific caspase-1 inhibitor, Z-YVAD-FMK, significantly suppressed the expression of pyroptosis pathway-related proteins, and reduced vascular inflammation and lesion development in an ApoE−/− mouse model of atherosclerosis. This evidence concerns the gene GSDMD and atherosclerosis.