BackgroundCoronary artery disease (CAD) is a multi-factor complex trait and is heritable, especially in early-onset families. However, the genetic factors affecting the susceptibility of early-onset CAD are not fully characterized.MethodsIn the present study, we identified a rare nonsense variant in theCYP17A1gene from a Chinese Han family with CAD. To validate the effect of this variation on atherosclerosis and early-onset coronary artery disease, we conducted studies on population, cells, and mice.ResultsThe mutation precisely congregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Similar to the human phenotype, theCYP17A1-deficient mice present the phenotype of metabolic syndrome with hypertension, increased serum glucose concentration, and presentation of central obesity and fatty liver. Furthermore,CYP17A1knockout mice orCYP17A1+ApoEdouble knockout mice developed more atherosclerotic lesions than wild type (WT) with high fat diary. In cell models,CYP17A1was found to be involved in glucose metabolism by increasing glucose intake and utilization, through activating IGF1/mTOR/HIF1-α signaling way, which was consistent inCYP17A1knockout mice with impaired glucose tolerance and insulin resistance.ConclusionsThrough our study of cells, mice and humans, we identifiedCYP17A1as a key protein participating in the pathophysiology of the atherosclerotic process and the possible mechanism ofCYP17A1C987X mutation induced atherosclerosis and early-onset CAD involving glucose homeostasis regulation was revealed.Video AbstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s12964-023-01061-z.