ALOXE3 encodes an atypical lipoxygenase with prominent hydroperoxide isomerase activity that catalyzes conversion of arachidonic and linoleic acid-derived hydroperoxides into hepoxilin-type epoxyalcohols and ketones 12. In skin, ALOXE3 acts downstream of ALOX12B to modify esterified omega-hydroxyacyl-sphingosine ceramides, producing epoxy-ketone derivatives essential for corneocyte lipid envelope synthesis and establishing the skin barrier to water loss 3. Loss-of-function mutations in ALOXE3 represent the second most common cause of autosomal recessive congenital ichthyosis (ARCI), with 27 pathogenic variants identified to date 4. ALOXE3 expression is significantly downregulated in both atopic dermatitis and psoriasis lesions, contributing to barrier dysfunction 5. Beyond dermatology, ALOXE3 variants in Dravet syndrome patients decrease gene expression and enzyme activity, suggesting involvement in arachidonic acid-pathway-mediated epileptogenesis 6. In cancer biology, ALOXE3 expression predicts poor prognosis in colon adenocarcinoma through ERK1/2 signaling pathway activation and modulation of tumor immune infiltration 7. Additionally, ALOXE3 contributes to diabetic kidney fibrosis via oxidative stress and scar-associated macrophage activation 8.