ALOX15B (arachidonate 15-lipoxygenase type B) is a lipid-peroxidizing enzyme that catalyzes polyunsaturated fatty acid oxygenation to generate hydroperoxy and hydroxy fatty acids 1. Unlike its murine ortholog Alox8 which exhibits 8-lipoxygenase activity, human ALOX15B catalyzes 15-position oxygenation of arachidonic acid with S-chirality specificity, utilizing both free and esterified fatty acids as substrates 12. Mechanistically, ALOX15B controls macrophage cholesterol homeostasis through lipid peroxidation-dependent activation of ERK1/2 signaling, which promotes SREBP2 nuclear localization and subsequent upregulation of sterol biosynthesis genes 3. In keratinocytes, ALOX15B suppresses inflammation via EGFR/JAK1/STAT1 pathway modulation and promotes specialized proresolving mediator biosynthesis 45. ALOX15B dysfunction associates with multiple diseases including atherosclerosis, psoriasis, atopic dermatitis, and pancreatic cancer 16. In KRAS-mutant pancreatic cancer, ALOX15B downregulation correlates with poor outcomes; restoration of ALOX15B membrane localization via disruption of ABHD17C-mediated depalmitoylation induces ferroptosis and tumor suppression 7. Dysregulated ALOX15B lipid mediator production contributes to psoriatic inflammation, while glucocorticoid-induced ALOX15B upregulation in macrophages promotes inflammatory resolution 45.