Leucine‐Dependent SLC7A5–PGAM5 Interaction Promotes Advanced Atherosclerosis Through Hindering Mitochondrial Function of Macrophages

Abstract The residual risks of advanced atherosclerosis remain substantial despite current preventive strategies and pharmacotherapy. Circulating branched‐chain amino acids are biomarkers of cardiovascular disease risk. However, the mechanism of leucine in atherosclerosis progression remains unclear. Leucine transporter‐SLC7A5‐mediated leucine intake that promotes advanced atherosclerosis in mice, increasing apoptotic macrophages and lipids accumulation within plaques. Multi‐omics analyses showed that leucine deprivation enhanced macrophage mitochondrial function and increased plaque CD5L hi macrophages, under SLC7A5‐deficiency‐mediated leucine deprivation, these cells exhibited stronger oxidative phosphorylation and lipid metabolism. Mechanistically, leucine deficiency reduced SLC7A5‐PGAM5 binding in macrophages, promoting PGAM5‐NDUFV1 interaction and enhancing mitochondrial function, which attenuates atherosclerosis progression. Collectively, these findings elucidate the function and mechanism of SLC7A5 in Cd5l hi macrophages, highlighting it as a potential therapeutic target. Strategies aimed at improving mitochondrial function also offer a promising approach for advanced atherosclerosis treatment.