PIK3R6 encodes a regulatory subunit of the PI3K gamma complex that plays crucial roles in cellular signaling and disease progression. As an adapter protein, PIK3R6 drives activation of PIK3CG by beta-gamma G protein dimers, though the PIK3CG:PIK3R6 heterodimer shows reduced sensitivity compared to PIK3CG:PIK3R5 and requires HRAS binding for membrane recruitment [UniProt]. The protein functions in angiogenesis by recruiting PI3K gamma complexes to PDE3B:RAPGEF3 signaling complexes [UniProt]. In cancer contexts, PIK3R6 demonstrates significant oncogenic properties across multiple tumor types. In clear cell renal cell carcinoma, PIK3R6 upregulation correlates with poor survival, and its knockdown reduces cell proliferation, migration, and invasion while inducing cell cycle arrest and apoptosis 1. Similarly, PIK3R6 promotes hepatocellular carcinoma angiogenesis through STAT3 signaling pathway activation 2. In ovarian cancer, PIK3R6 serves as a target of RBBP6, mediating proliferation and metastasis 3. PIK3R6 also participates in trophoblast function, where its downregulation contributes to preeclampsia pathogenesis through suppressed STAT3 phosphorylation 4. Bioinformatics analyses identify PIK3R6 as a hub gene in metabolic dysfunction-associated steatotic liver disease, highlighting its involvement in PI3K/AKT signaling 5.