DGKI encodes a diacylglycerol kinase that catalyzes the conversion of diacylglycerol (DAG) into phosphatidic acid (PA), thereby acting as a molecular switch between two distinct lipid signaling pathways with opposing cellular effects. By controlling DAG-mediated activation of RASGRP3, DGKI negatively regulates Rap1 signaling and may modulate presynaptic DAG signaling during glutamate receptor-dependent long-term depression. The enzyme localizes to synaptic and cytoplasmic compartments where it influences intracellular signaling networks. DGKI variants associate with multiple complex traits and diseases. Genetic variants at the DGKI locus show evidence of positive selection in PCOS susceptibility 1, and SNP variations in the chromosome 7 region containing DGKI are associated with dyslexia in Finnish and German populations 2. DGKI has been identified as a high-scoring candidate gene in over 500 BMI-associated loci 3, and methylation of DGKI associates with COPD severity in airway epithelium 4. In cancer contexts, DGKI methylation serves as a biomarker for glioblastoma (GBM) prognosis: MGMTmethylated/DGKImethylated tumors correlate with poor outcomes, whereas selective DGKI demethylation via targeted DNMT1/ELK1 disruption restores temozolomide sensitivity 5 6. Lower DGKI expression associates with worse survival in thyroid carcinoma 7. Beyond oncology, DGK inhibition reduces airway smooth muscle proliferation relevant to asthma pathogenesis 8, and DGK inhibitors enhance tumor-infiltrating lymphocyte function in immunotherapy contexts 9.