Natural Products Modulate Plaque Macrophage Functional Programs in Atherosclerosis

Abstract

Abstract Atherosclerosis is a chronic inflammatory and immunometabolic disease in which plaque macrophages integrate lipid-derived danger signals, metabolic stress and cell-death cues to shape foam-cell formation, necrotic-core expansion, fibrous-cap integrity and plaque vulnerability. Moving beyond the conventional M1/M2 paradigm, this review conceptualizes plaque macrophages as dynamic functional states organized around interconnected programs of inflammatory sensing, immunometabolic remodeling, lipid uptake and cholesterol efflux, efferocytosis and inflammation resolution, and intracellular quality control involving autophagy, mitophagy, inflammasome activation and pyroptosis. Within this framework, natural products, phytochemicals and traditional formulas are discussed as multi-level modulators of macrophage function and plaque remodeling. Their effects converge on limiting inflammatory amplification, restoring metabolic and lipid homeostasis, enhancing clearance of dying cells, preserving mitochondrial and lysosomal integrity, and reducing inflammatory cell death. By linking macrophage functional reprogramming with plaque composition and stability, this review provides an integrated mechanistic framework for understanding the anti-atherosclerotic actions of natural products and highlights their potential as complementary strategies for targeting residual inflammatory and plaque-related risk.