Here, we combined genetic causal analysis with <i>in vivo</i>/<i>in vitro</i> experiments to explore the therapeutic efficacy of PCSK9 inhibition against CAC and the mediating role of fibroblast growth factor 23 (FGF23) in this process.<h4>Methods</h4>First, we used two-sample Mendelian randomization (MR) and multivariable Mendelian randomization to identify lipid profiles genetically associated with coronary artery calcification. Here, PCSK9 is linked to coronary artery calcification.