PIK3R3 is a regulatory subunit of phosphoinositide-3-kinase (PI3K) that modulates PI3K/AKT signaling through multiple mechanisms. As a regulatory protein, PIK3R3 binds to activated protein-tyrosine kinases via its SH2 domain and regulates their kinase activity, particularly during insulin stimulation when it binds to IRS-1 1. PIK3R3 functions in diverse cellular contexts: it regulates tight junction integrity through the NF-κB pathway in intestinal epithelial cells 1, controls stem cell differentiation and senescence via FOXO1 modulation 2, and mediates NMDAR-dependent AKT signaling for memory updating in neurons 3. Dysregulation of PIK3R3 is implicated in multiple diseases. In inflammatory bowel disease, PIK3R3 overexpression disrupts tight junction protein ZO-1 expression and increases intestinal permeability; PIK3R3 inhibition ameliorates disease symptoms in mouse models 1. PIK3R3 amplification occurs in pancreatic cancer as a focal oncogenic event 4, while miR-511-mediated PIK3R3 suppression inhibits hepatocellular carcinoma progression via the AKT/mTOR pathway 5. Notably, CARD11-PIK3R3 gene fusions enhance therapeutic T cell efficacy in cancer immunotherapy 6. PIK3R3 variants show protective associations against liver cancer in Chinese populations 7. VHL loss in renal cell carcinomas stabilizes PIK3R3 mRNA through m6A modification, promoting oncogenic PI3K signaling 8.