Atherosclerosis, a leading cause of cardiovascular disease, is a complex, multifactorial disorder involving lipid accumulation, chronic inflammation, immune dysregulation, and metabolic disturbances. Recent advances highlight critical roles for the Stimulator of Interferon Genes (STING) pathway, macrophage immunometabolism (the metabolic reprogramming of immune cells), oxidative DNA damage, neutrophil heterogeneity, sex disparities, and interactions with the gut microbiome and non-coding RNAs (molecules that regulate gene expression without coding for proteins). This integrative review synthesizes current knowledge from molecular, immunological, and epidemiological perspectives to illuminate key mechanisms in atherogenesis. We critically examine emerging mechanistic insights, including STING-mediated inflammation and macrophage metabolic reprogramming, and their roles in plaque initiation and progression. The review further evaluates novel therapeutic approaches, ranging from established lipid-lowering agents (e.g., statins, PCSK9 inhibitors, inclisiran, and bempedoic acid) to anti-inflammatory strategies (e.g., IL-1β and IL-6 inhibitors) and potential STING-targeted interventions. By integrating recent discoveries across basic and clinical science, this review emphasizes the need for personalized, multi-targeted therapies addressing inflammation, metabolism, and immune signaling. We propose a research roadmap prioritizing translational studies that link molecular mechanisms to clinical outcomes, ultimately aiming to improve prevention and management of atherosclerotic cardiovascular disease.
Keywords: Atherosclerosis; PCSK9; STING; cardiovascular; inflammation; lipid; plaque; therapeutic.
Copyright: © 2025 Saudi Journal of Medicine & Medical Sciences.