12-LOX

12-Lipoxygenase (12-LOX) catalyzes the oxygenation of arachidonic acid and other polyunsaturated fatty acids, generating bioactive lipid mediators that regulate cellular signaling and inflammation^[1][2]. Mechanistically, platelet 12-LOX is activated via the collagen receptor glycoprotein VI (GPVI) and downstream src-tyrosine kinases, PI3-kinase, and Ca²⁺ mobilization, while PKC inhibition potentiates its activity^[3]. 12-LOX exhibits isoform-specific functions distinct from 15-LOX and 5-LOX, including intrinsic hepoxilin A₃ synthase activity and selective platelet oxylipin production^[4][5][6]. In disease models, 12-LOX contributes to diabetes pathogenesis through modulation of β-cell inflammation and to neuroinflammation by activating NLRP3 inflammasomes^[1][7][8][2]. Isoform-targeted inhibitors, such as ML351 for 12/15-LOX, reduce ischemia-induced lipid peroxidation, cytokine release, and inflammasome activation, highlighting its experimental relevance^[7][8]. Additionally, dietary polyunsaturated fatty acids, including dihomo-γ-linolenic acid, serve as substrates for 12-LOX-mediated generation of anti-thrombotic oxylipins, providing mechanistic insight into vascular protection^[5]. Comparative studies indicate that 12-LOX activity is distinct in substrate specificity, signaling regulation, and physiological outcomes from related LOX isoforms, facilitating selective pharmacological intervention and functional studies in cellular and animal models^[9][4][5][7].