Atherosclerosis has traditionally been considered a lipid-driven disease. However, emerging evidence highlights the central role of inflammation in the development of atherosclerosis. Multiple cell types, including endothelial cells, macrophages, and other immune cells, interact within lesions to form a chronic inflammatory microenvironment. Unhealthy lifestyle, smoking and metabolic disorders like hyperlipidemia, hyperglycemia, and their derived pro-atherogenic products drive vascular inflammation. Recent evidence reveals that high-sensitivity C-reactive protein surpasses LDL-cholesterol in predicting future cardiovascular risk. Combining lipid-lowering with anti-inflammatory therapies significantly reduces event recurrence, underscoring the need for targeted drugs. Promising results have emerged from trials of anti-inflammatory agents. Statins and other lipid-lowering drugs also exhibit anti-inflammatory properties. However, cholesterol-independent strategies face challenges like infection risk from immunosuppression, requiring extensive safety evaluation. Enhancing intrinsic resilience mechanisms is a promising alternative in combating vascular inflammation and atherosclerosis. High-throughput screening accelerates drug development, while induced pluripotent stem cell-derived vascular organoids better simulate human atherosclerosis pathobiology, improving preclinical predictions. Research on organ interaction networks and trained immunity offers novel therapeutic targets. In this comprehensive review, we provide a state-of-the-art synthesis of the drivers, mechanisms, and potential therapies of atherosclerosis by targeting inflammation, with an aim to reducing residual cardiovascular risk in the post-statin era.

Atherosclerosis  /  Inflammation  /  Mechanisms  /  Therapies  /  Drug discovery  /  Endothelial cells  /  Cardiovascular risk factors  /  Clinical trials