Background <p>Smooth muscle-derived foam cell formation is a key to atherosclerosis (AS) development. Mitochondrial damage is involved in AS pathogenesis S. Here, effects of ZDHHC5 on mitochondrial damage and foam cell formation of vascular smooth muscle cells were evaluated.</p> Methods <p>Expressions of mRNA and protein were determined by RT-qPCR and Western blot. ORO and Nile red staining evaluated foam cell formation. Mito tracker Green and Mito Tracker Red probes evaluated mitochondrial integrity. Electron microscopy observed mitochondrial morphology. Cytoplasmic mtDNA was quantified by mtDNA release assay. Acyl-biotin exchange assay tested palmitoylation level. Co-immunoprecipitation (Co-IP) detected interaction between ZDHHC5 and NLRP3. RNA immunoprecipitation (RIP) and RNA pull down verified interaction between ZDHHC5 and IGF2BP1. Methylated RNA immunoprecipitation (MeRIP) assessed m6A level on ZDHHC5. ApoE^−/− mouse model of AS was constructed. Histological analysis of atherosclerotic lesions was performed. Levels of IL-1β and IL-18 in serum were detected by ELISA.</p> Results <p>NLRP3 depletion reduced damage to mitochondria within foam cells derived from smooth muscle. Inhibiting NLRP3 palmitoylation hindered NLRP3 inflammasome activation. ZDHHC5 triggered NLRP3 activation through enhancing NLRP3 palmitoylation. ZDHHC5 exacerbated mitochondrial damage via activating NLRP3 inflammasome. IGF2BP1 enhanced stability and expression of ZDHHC5 mRNA in a m6A-dependent way. IGF2BP1 triggered NLRP3-mediated mitochondrial damage and amplified AS by upregulating ZDHHC5 in ApoE^−/− mice. IGF2BP1, ZDHHC5, and NLRP3 function as biomarkers for early detection of AS.</p> Conclusions <p>IGF2BP1 regulates ZDHHC5-mediated NLRP3 inflammasome activation, thereby enhancing mitochondrial damage and foam cell formation in vascular smooth muscle cells, which provides new therapeutic targets for AS.</p>