Cardio-Immunologic Interfaces in Systemic Lupus Erythematosus: Molecular Heterogeneity, Autoantibody-Driven Endothelial Injury, Complement Cascade Dysregulation, and Emerging Precision Strategies for Lupus-Associated Cardiovascular Disease

Abstract Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by profound immune dysregulation, leading to multi-organ involvement. Cardiovascular disease (CVD) has emerged as the leading cause of morbidity and mortality in SLE, with a 7- to 10-fold increased risk of atherosclerotic events and even higher risk in young women. This review elucidates the cardio-immunologic interfaces in SLE, emphasizing molecular heterogeneity, autoantibody-mediated endothelial injury, complement cascade dysregulation, and other key mechanisms such as type I interferon signaling and neutrophil extracellular trap (NET) formation. We discuss how these pathways accelerate endothelial dysfunction, promote premature atherosclerosis, microvascular disease, myocarditis, and valvular involvement. Finally, we highlight emerging precision medicine strategies, including B-cell targeted therapies (belimumab), type I interferon blockade (anifrolumab), calcineurin inhibition (voclosporin), complement modulators, and CD19-directed CAR-T cell therapy, which offer disease-modifying potential beyond traditional immunosuppression. A personalized, multidisciplinary approach integrating cardiovascular risk stratification, biomarker-guided therapy, and novel biologics is essential to mitigate the CVD burden in SLE. (248 words) Keywords: systemic lupus erythematosus, cardiovascular disease, endothelial injury, autoantibodies, complement system, precision medicine, CAR-T therapy, interferon