DIRAS3 is a maternally imprinted tumor suppressor gene encoding a 26 kDa GTPase with 60% homology to RAS and a distinctive 34-amino acid N-terminal extension 1. As a unique endogenous RAS inhibitor, DIRAS3 binds directly to RAS, disrupting RAS dimers and clusters to block RAS/MAPK signaling 2. DIRAS3 also inhibits PI3K/AKT and JAK/STAT pathways 1. Loss of DIRAS3 expression occurs frequently in ovarian, breast, lung, prostate, colon, brain, and thyroid cancers through methylation and deletion mechanisms 13. Reexpression of DIRAS3 inhibits cancer cell growth and motility while preventing angiogenesis 1. DIRAS3 is essential for autophagy induction through multiple mechanisms, including activation of the STK11/LKB1-PRKAA/AMPK pathway in KRAS-mutant cancers 4. DIRAS3 induces tumor dormancy in vivo and mediates ROS-dependent apoptosis in KRAS-driven pancreatic and ovarian carcinomas 14. Notably, fibronectin in the tumor microenvironment can inhibit DIRAS3-induced autophagy through integrin β1/FAK/AKT signaling 5. In high-grade gliomas, DIRAS3 upregulation paradoxically promotes immune evasion and poor prognosis 6. DIRAS3 expression in dormant, autophagic cancer cells serves as a prognostic biomarker and therapeutic target.