Cholesterol-Inflammation Fusion Hypothesis in Atherosclerosis: An Evolving Paradigm in Pathogenesis and Therapy

Atherosclerosis (AS) remains the leading cause of cardiovascular morbidity and mortality worldwide despite advances in multidimensional prevention and treatment. We propose a novel cholesterol-inflammation fusion hypothesis, a unifying framework that conceptualizes AS as a self-perpetuating disease driven by the bidirectional and synergistic interplay between dysregulated cholesterol metabolism and chronic vascular inflammation. Mechanistically, cholesterol crystals, oxidized low-density lipoprotein, and aggregated low-density lipoprotein promote macrophage and vascular smooth muscle cell lipid accumulation and activate inflammatory signaling, whereas cytokines impair cholesterol efflux and amplify lipid accumulation. Clinical evidence demonstrates that controlling either lipid or inflammatory pathways alone leaves residual risk, whereas simultaneous regulation yields the greatest benefit. This paradigm provides a conceptual basis for dual-target therapeutic strategies. This review outlines mechanistic insights and translational implications of this fusion hypothesis, aiming to guide future precision risk stratification and therapy design in atherosclerotic cardiovascular disease.