Systemic lupus erythematosus–driven accelerated atherosclerosis: the immune–metabolic–vascular axis and therapeutic implications

Patients with systemic lupus erythematosus (SLE) are at markedly increased risk of premature atherosclerosis (AS) and atherosclerotic cardiovascular disease (ASCVD), and this excess risk is not fully explained by traditional Framingham factors. Increasing evidence suggests that SLE does not merely coexist with AS; rather, persistent immune activation and immunometabolic dysregulation reshape the vascular microenvironment toward endothelial dysfunction, lipoprotein impairment, maladaptive myeloid activation, and immunothrombosis. This review synthesizes current epidemiologic, mechanistic, and translational evidence supporting an immune–metabolic–vascular framework for SLE-accelerated AS. We focus on four interconnected processes: (1) type I interferon (IFN-I)-associated endothelial injury and defective vascular repair; (2) neutrophil extracellular traps (NETs) and oxidative modification of high-density lipoprotein, contributing to dysfunctional or pro-inflammatory HDL; (3) monocyte/macrophage immunometabolic reprogramming, which favors foam-cell formation and inflammasome activation; and (4) T- and B-cell metabolic disequilibrium, which sustains vascular inflammation and autoantibody-driven immune injury. Across these pathways, metabolic rewiring appears to function not merely as a parallel phenomenon, but as a shared amplifier linking systemic autoimmunity to lesion-level vascular progression. Recognizing these shared checkpoints has therapeutic implications. These observations suggest that future strategies may need to integrate upstream metabolic resetting, midstream immune-specific blockade, and downstream lipid or vascular-wall protection, rather than relying solely on lipid lowering or broad immunosuppression. However, most available evidence remains confined to mechanistic studies, biomarker readouts, or surrogate vascular endpoints, and dedicated trials with plaque or cardiovascular event outcomes are still needed.