GDI2 (GDP dissociation inhibitor 2) is a negative regulator of Rab GTPases that maintains these small GTPases in their inactive GDP-bound state, thereby controlling intracellular membrane trafficking and vesicle transport 1. Mechanistically, GDI2 extracts Rab GTPases from membranes to the cytoplasm; however, itaconate can alkylate critical cysteine residues on GDI2 (positions 203, 335, and 414), impairing this extraction function and promoting Rab retention on membranes 2. GDI2 also negatively regulates ciliogenesis through inhibition of RAB8A 1. Clinically, elevated GDI2 expression is associated with poor prognosis across multiple cancers. In hepatocellular carcinoma, high GDI2 correlates with aggressive tumor features and worse survival, functioning through lipid metabolism and extracellular matrix pathways 3. In breast cancer, GDI2 cooperates with RAB5/RAB7A to regulate αVβ6-HER2 cross-talk and invasion, with dysregulated GDI2 recruitment contributing to trastuzumab resistance 4. In prostate cancer, paclitaxel inhibits GDI2 expression to suppress proliferation via p75NTR pathway activation 5. Conversely, GDI2 deletion ameliorates Alzheimer's disease pathology by altering amyloid precursor protein trafficking and reducing amyloid-β production 6. Small-molecule GDI2 inhibitors show promise for inducing paraptosis in pancreatic cancer 7.