GNAI2 encodes G protein subunit alpha i2, a component of heterotrimeric G protein signal transduction that regulates adenylyl cyclase and intracellular cAMP levels 1. GNAI2 couples G protein-coupled receptors to downstream signaling pathways, including TCR signaling where activating mutations enhance ERK/MAPK and PI3K-AKT signaling through RASA2 sequestration 2. Post-translational modification via S-nitrosylation at Cysteine 66 enables GNAI2-CXCR5 coupling to suppress Hippo pathway kinase LATS1, promoting YAP-dependent endothelial inflammation in diabetes-accelerated atherosclerosis 3. GNAI2 has emerging roles in multiple diseases. In nonalcoholic steatohepatitis (NASH), GNAI2 upregulation exacerbates disease by binding peroxiredoxin 1 and promoting inflammation and lipid accumulation; GNAI2 inhibition restores lipophagy 4. In colitis-associated colorectal cancer, elevated GNAI2 in dendritic cells drives IL6-mediated myeloid-derived suppressor cell expansion and tumorigenesis 5. GNAI2 is downregulated in early-stage ovarian cancer (54% average reduction) but upregulated in advanced disease, correlating with CREB deregulation and metastatic potential 1. In diabetic nephropathy, GNAI2 acts downstream of C5aR1 in macrophages to promote renal inflammation 6. GNAI2 mutations also associate with Burkitt lymphoma pathogenesis 7 and serve as negative prognostic biomarkers in cholangiocarcinoma 8. These findings position GNAI2 as a multifunctional signaling hub with therapeutic potential across inflammatory and malignant diseases.