Exercise-induced lactylation of MeCP2 K271 promotes atherosclerosis regression by enhancing M2 macrophage polarization. This study reveals that exercise reduces atherosclerosis in ApoE $ ^{-/-} $ mice through the lactylation of MeCP2 K271, which promotes pro-repair M2 macrophage polarization, reduces plaque area, shrinks necrotic cores, decreases lipid deposition, and increases collagen content. Lactylation of MeCP2 K271 is mediated by P300 and regulated by HDAC3. The interaction between MeCP2 K271 lactylation and H3K36me3 leads to increased chromatin accessibility and transcriptional repression of RUNX1, promoting M2 macrophage polarization and plaque stability. Pharmacological inhibition of RUNX1 enhances atheroprotective effects by promoting M2 macrophage polarization. These findings suggest that interventions enhancing MeCP2 K271 lactylation can promote plaque stabilization and reduce the risk of atherosclerotic cardiovascular disease. The study also identifies RUNX1 as a potential drug target for exercise therapy.Exercise-induced lactylation of MeCP2 K271 promotes atherosclerosis regression by enhancing M2 macrophage polarization. This study reveals that exercise reduces atherosclerosis in ApoE $ ^{-/-} $ mice through the lactylation of MeCP2 K271, which promotes pro-repair M2 macrophage polarization, reduces plaque area, shrinks necrotic cores, decreases lipid deposition, and increases collagen content. Lactylation of MeCP2 K271 is mediated by P300 and regulated by HDAC3. The interaction between MeCP2 K271 lactylation and H3K36me3 leads to increased chromatin accessibility and transcriptional repression of RUNX1, promoting M2 macrophage polarization and plaque stability. Pharmacological inhibition of RUNX1 enhances atheroprotective effects by promoting M2 macrophage polarization. These findings suggest that interventions enhancing MeCP2 K271 lactylation can promote plaque stabilization and reduce the risk of atherosclerotic cardiovascular disease. The study also identifies RUNX1 as a potential drug target for exercise therapy.