J Lipid Res. 2026 Oct 14:101172. doi: 10.1016/j.jlr.2026.101172. Online ahead of print.
ABSTRACT
12/15-Lipoxygenase (12/15-LOX), a key oxidoreductase enzyme, catalyzes the peroxidation of polyunsaturated fatty acids (PUFAs) including omega-6 and omega-3 fatty acids. This enzyme is expressed in multiple cell types such as macrophages, endothelial cells, and epithelial cells, where it participates in arachidonic acid (AA) metabolism through the hydroperoxidation pathway. The catalytic activity of 12/15-LOX generates bioactive lipid mediators, notably 12-hydroxyeicosatetraenoic acid (12-HETE) and 15-hydroxyeicosatetraenoic acid (15-HETE), which serve as signaling molecules in physiological and pathological processes. Emerging evidence establishes 12/15-LOX as a critical mediator in oxidative stress and inflammatory cascades. Its pathophysiological involvement has been mechanistically linked to the pathogenesis of cardiovascular disorders, particularly through promoting atherosclerotic plaque formation, vascular endothelial dysfunction, and myocardial ischemic injury. Clinical epidemiological studies further demonstrate significant associations between 12/15-LOX activity and disease progression in atherosclerosis, essential hypertension, and acute myocardial infarction. In this review, we systematically examine the biosynthetic origin of 12/15-LOX, delineate its metabolic pathways and its pleiotropic functions in modulating inflammatory responses, redox homeostasis, and programmed cell death cascades. Furthermore, we critically evaluate emerging therapeutic strategies targeting 12/15-LOX enzymatic activity or its downstream effectors, with particular emphasis on translational opportunities for cardiovascular disease management. This synthesis aims to advance the development of precision therapies targeting the 12/15-LOX pathway in cardiometabolic disorders.
PMID:42874872 | DOI:10.1016/j.jlr.2026.101172