An Update of Oxidative Stress in Atherosclerosis with Emphasis on the LOX-1-NLRP3 Inflammasome Axis.

purpose of reviewAtherosclerosis is a chronic inflammatory disease in which oxidative stress serves as a final common mechanism linking endothelial injury, lipoprotein oxidation, immune activation, and plaque progression. Since the original description of reactive oxygen species (ROS) generating and antioxidant systems in atherogenesis, substantial advances have reshaped the mechanistic and therapeutic landscape. This review provides a comprehensive update on oxidative stress in atherosclerosis, with particular emphasis on the LOX-1-NLRP3 inflammasome axis as a central driver of residual inflammatory risk. RECENT

findingsThe lectin-like oxidized LDL receptor-1 (LOX-1) has been established as a regulated, druggable node through the identification of TRIM31-mediated ubiquitination. The first-in-human LOX-1 antibody trial (GOLDILOX-TIMI 69) demonstrated near-complete soluble LOX-1 suppression and IL-6 reduction, though plaque regression was not achieved. The mechanistic cascade linking LOX-1 activation to mitochondrial DNA damage, impaired autophagy, and NLRP3 inflammasome-driven IL-1β release now provides a molecular explanation for persistent vascular inflammation even when LDL-C targets are met with high-intensity statins and PCSK9 inhibitors. Clinical validation of the inflammation hypothesis through CANTOS, COLCOT, and LoDoCo2 has led to FDA approval of colchicine for secondary cardiovascular prevention. Emerging evidence implicates clonal hematopoiesis, vascular senescence, and the senescence-associated secretory phenotype as amplifiers of oxidative-inflammatory signaling in the vessel wall. The LOX-1-NLRP3 axis represents an important mechanistic advance since the original characterization of oxidative stress in atherosclerosis. Future strategies, including direct NLRP3 inhibitors, longer-duration LOX-1 antibody trials, biomarker-guided combination therapy, and mitochondria-targeted antioxidants, aim to close the residual inflammatory risk gap that persists despite optimal lipid-lowering therapy.