This study investigates the role of methyl-CpG-binding protein 2 (MeCP2) K271 lactylation in the atheroprotective effects of exercise. Using an ApoE-/- mouse model, the authors found that exercise-induced lactylation of MeCP2 at lysine 271 (K271) promotes pro-repair M2 macrophage polarization, reducing plaque area, shrinking necrotic cores, and increasing collagen content. Mechanistically, MeCP2 K271 lactylation interacts with H3K36me3, leading to increased chromatin accessibility and transcriptional repression of RUNX1, a key regulator of atherosclerosis. Pharmacological inhibition of RUNX1 also exhibits atheroprotective effects by promoting M2 macrophage polarization. The study concludes that MeCP2 K271 lactylation-H3K36me3/RUNX1 plays a critical role in atherosclerosis development, and RUNX1 is identified as a potential drug target for exercise therapy.This study investigates the role of methyl-CpG-binding protein 2 (MeCP2) K271 lactylation in the atheroprotective effects of exercise. Using an ApoE-/- mouse model, the authors found that exercise-induced lactylation of MeCP2 at lysine 271 (K271) promotes pro-repair M2 macrophage polarization, reducing plaque area, shrinking necrotic cores, and increasing collagen content. Mechanistically, MeCP2 K271 lactylation interacts with H3K36me3, leading to increased chromatin accessibility and transcriptional repression of RUNX1, a key regulator of atherosclerosis. Pharmacological inhibition of RUNX1 also exhibits atheroprotective effects by promoting M2 macrophage polarization. The study concludes that MeCP2 K271 lactylation-H3K36me3/RUNX1 plays a critical role in atherosclerosis development, and RUNX1 is identified as a potential drug target for exercise therapy.