ASCL4 (achaete-scute family bHLH transcription factor 4) is a transcriptional regulator with primary functions in ferroptosis regulation and fatty acid metabolism. ASCL4 encodes long-chain acyl-CoA synthase 4, an enzyme that esterifies CoA into polyunsaturated fatty acids, particularly arachidonic acid, which triggers ferroptosis execution through phospholipid peroxidation 1. ASCL4 functions as a positive regulator of ferroptosis while also modulating phospholipid membrane composition and eicosanoid biosynthesis 1. Mechanistically, ASCL4 expression is upregulated in ferroptotic pathways: α-synuclein stimulation activates ferroptosis genes including ASCL4 via STAT3 inhibition in microglia 2, and MLL1 epigenetically promotes ASCL4 expression during placental ferroptosis in preeclampsia 3. ASCL4 also mediates chemoresistance through STAT3-dependent phospholipid synthesis enhancement, protecting mitochondrial integrity 4. Disease relevance spans multiple pathologies: ferroptosis dysregulation in ulcerative colitis 5, renal fibrosis 6, Alzheimer's disease 7, and KRAS-mutant pancreatic cancer 8. Clinically, modulating ASCL4 represents a therapeutic strategy—inhibiting ASCL4 sensitizes tumors to ferroptosis and immunotherapy, while controlling ASCL4 levels via autophagy-mediated degradation improves drug responsiveness 8.