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Gene-regulatory networks (GRNs) offer a mechanistic framework for dissecting the complex molecular and genetic architecture of coronary artery disease and for identifying new therapeutic opportunities. Here, we present a GRN-driven drug-repurposing strategy that integrates transcriptional signatures induced by silencing key drivers of the human arterial wall foam cell regulator GRN 42 with drug-induced gene expression profiles from the NIH LINCS program. In vitro screening of top candidate compounds validates the computational predictions, identifying candidate foam cell modulators and showing that auranofin, an FDA-approved gold salt used to treat rheumatoid arthritis, effectively reduces foam cell formation. In vivo, auranofin attenuates atherosclerosis and inflammation in both male mice and rabbits. Clinically, auranofin was associated with reduced cardiovascular risk in a retrospective cohort of patients with rheumatoid arthritis. Together, these findings show that a GRN-based drug-repurposing framework, coupled with preclinical and clinical validation, can uncover new therapeutic applications for existing drugs, including auranofin, in coronary artery disease.