TRIM31–LOX‐1 Axis: A Novel Therapeutic Frontier in Atherosclerosis

ABSTRACT Atherosclerosis, driven by a vicious cycle of lipid accumulation and chronic inflammation, underlies most cardiovascular diseases. Macrophages exacerbate this process by internalizing oxidized low‐density lipoprotein (oxLDL), forming foam cells, and releasing inflammatory mediators. A recent study published in Circulation identified the TRIM31–LOX‐1 axis as a critical regulatory pathway in atherosclerosis. TRIM31, an E3 ubiquitin ligase enriched in macrophages, catalyzes K48‐linked polyubiquitination of LOX‐1 at lysine 12 (K12), targeting it for proteasomal degradation. This reduces lipid uptake, foam cell formation, and inflammatory signaling, thereby attenuating plaque progression. The TRIM31–LOX‐1 interaction is enhanced by oxLDL and conserved in human macrophages. Functional studies confirmed the necessity of LOX‐1 K12 and demonstrated the dependence of TRIM31's athero‐protection on LOX‐1. These findings establish the TRIM31–LOX‐1 axis as a central ubiquitin‐mediated pathway in macrophage‐driven atherogenesis, offering a novel target for immunometabolic therapy. Future directions include elucidating LOX‐1 regulation, evaluating its biomarker potential, and developing cell‐specific delivery strategies for translational application.