ALDH1A3 catalyzes the NAD-dependent oxidation of all-trans-retinal to all-trans-retinoate, a critical lipid for embryonic eye and nasal development 1. Beyond its classical role in retinoic acid biosynthesis, ALDH1A3 exhibits multifunctional roles in disease pathogenesis through nuclear localization and metabolic reprogramming. In pulmonary arterial hypertension, nuclear ALDH1A3 converts acetaldehyde to acetate, generating acetyl-CoA for histone H3K27 acetylation to promote smooth muscle cell proliferation and glycolysis 2. In melanoma, ALDH1A3 partners with ACSS2 to couple acetaldehyde metabolism with histone acetylation of neural crest lineage genes, driving transcriptional heterogeneity and therapy resistance 3. ALDH1A3 overexpression confers therapeutic resistance in glioblastoma by enhancing PKM2 tetramerization and lactate-dependent DNA repair 4, while in colorectal cancer, AHR-mediated ALDH1A3 upregulation inhibits ferroptosis through NADH production 5. In pancreatic ductal adenocarcinoma, ALDH1A3 drives basal-like subtype through AP-1/RUNX2-mediated chr15 remodeling 6. ALDH1A3 serves as a cancer stem cell marker associated with poor prognosis 7, while ALDH1A3 expression in pancreatic islets correlates with beta cell dedifferentiation in type 2 diabetes 8. Mutations in ALDH1A3 cause isolated microphthalmia-8.