PDPK1 (3-phosphoinositide-dependent protein kinase 1) is a serine/threonine kinase that functions as a key activator of the PI3K/AKT signaling pathway with critical roles in cancer progression and metabolic regulation. Primary Function: PDPK1 catalyzes phosphorylation of AKT at threonine 308, a crucial step for AKT activation 1. The kinase also phosphorylates downstream effectors including phosphoglycerate kinase 1 (PGK1) to enhance tumor cell glycolysis 2. Mechanism: PDPK1 activation is regulated by multiple signals including copper binding via copper transporter 1 (CTR1) 3, α-ketoglutarate from glutaminolysis via histone demethylase KDM6A-mediated epigenetic regulation 4, and protein interactions facilitated by transmembrane proteins like TM4SF1 5. GSDME-derived protein fragments interact with PDPK1 to activate PI3K-AKT signaling in macrophages 6. PDPK1 protein stability is regulated through lysosomal-dependent degradation mechanisms involving aquaporin-mediated pathways 7. Disease Relevance: PDPK1 overexpression promotes multiple cancer types including hepatocellular carcinoma, glioblastoma, and breast cancer through enhanced proliferation and metabolic reprogramming 234. PDPK1 upregulation also contributes to immunotherapy resistance and tumor senescence evasion 65. In non-malignant disease, PDPK1 elevation promotes alcoholic steatohepatitis progression 8. Clinical Significance: PDPK1 inhibition or targeted suppression represents a therapeutic strategy for enhancing anti-PD-1 immunotherapy efficacy and protecting against alcohol-induced liver disease 865.