HACL2 (2-hydroxyacyl-CoA lyase 2) is an endoplasmic reticulum enzyme that catalyzes the C1 removal (cleavage) reaction in fatty acid α-oxidation via a thiamine pyrophosphate-dependent mechanism 1. The enzyme plays a major role in metabolizing 2-hydroxy fatty acids, particularly very-long-chain types, to generate odd-chain fatty acids that are incorporated into sphingolipids 2. HACL2 is essential for phytosphingosine degradation, converting 2-hydroxy palmitic acid to pentadecanoic acid through sequential α-oxidation reactions distinct from peroxisomal pathways 1. Beyond lipid metabolism, HACL2 exhibits acetolactate synthase-like activity, catalyzing dimethylglyoxal formation from lactate-derived pyruvate in diabetes 3. This dimethylglyoxal accumulation induces lysine adducts (Nε-3-hydroxy-2-butanonelysine), oxidative stress, and blood-brain barrier disruption, contributing to neurological complications in diabetes 3. HACL2 knockout mice show reduced odd-chain lipids and accumulated 2-hydroxy lipids in multiple tissues, with the most prominent effects in brain ceramides and stomach ceramides 2. These findings suggest HACL2 has dual roles: supporting normal lipid homeostasis and mediating pathological metabolite formation in diabetes-associated neurological disease.