PPP1R3B Suppresses Atherosclerosis by Promoting the M2 Polarization of Macrophages Through Glycogen Metabolic Reprogramming

Abstract Identifying targets that promote M2 macrophage polarization in the hypoxic plaque microenvironment is crucial for modulating immune metabolism and optimizing energy dynamics in atherosclerotic cardiovascular disease (ASCVD) treatment. The high phagocytic activity of M2 macrophages reduces foam cell formation. Their secretion of anti‐inflammatory cytokines enhances plaque stability, mitigating atherosclerosis progression. Through high‐throughput sequencing and multi‐omics bioinformatics analysis, protein phosphatase 1 regulatory subunit 3B ( PPP1R3B ) is identified as a key regulator linking glycogen metabolism to macrophage polarization. The integrated approach combined transcriptomic analysis of human atherosclerotic plaques (GSE57614) with RNA‐seq of PPP1R3B ‐modulated macrophages, revealing its dual role. PPP1R3B induces anti‐inflammatory M2 macrophage polarization and maintains energy supply in plaques. Its absence accelerates plaque progression. PPP1R3B regulates M2 macrophage polarization and energy metabolism via phosphorylated STAT3 (p‐STAT3), which plays a dual role by activating anti‐inflammatory transcriptional programs through the PPAR‐γ/PGC‐1α/CD206 axis in the nucleus and enhancing glycogenolysis‐mediated metabolic activity via the p‐GSK‐3β/p‐PYGL/p‐GYS2 axis in mitochondria. STAT3 plays a dual role in metabolic regulation and macrophage phenotype modulation. By orchestrating glycogen metabolic reprogramming, PPP1R3B ‐induced M2 polarization presents a novel strategy for anti‐ASCVD drug development, with significant potential for clinical translation.