PIK3R5 encodes a regulatory subunit of the class IB phosphoinositide 3-kinase (PI3K) complex, specifically the PI3Kγ isoform. It is required for recruitment of the catalytic subunit to the plasma membrane through interaction with Gβγ subunits and mediates G protein-coupled receptor signaling. Beyond this canonical role, PIK3R5 functions in immune regulation and cell survival pathways. PIK3R5 mutations cause ataxia with oculomotor apraxia type 3 (AOA3), an autosomal recessive cerebellar syndrome 1. The gene is implicated in multiple cancer contexts: in acute leukaemias, activated PIK3R5 promotes a noncanonical PI3Kγ-PAK1 axis that supports mitochondrial oxidative phosphorylation, and selective PI3Kγ inhibition with eganelisib is effective in this setting 2. In acute myeloid leukemia specifically, the myeloid-restricted PIK3CG/p110γ–PIK3R5/p101 axis drives Akt signaling; proteolysis-targeting chimera degradation of PIK3CG shows promise combined with venetoclax 3. PIK3R5 also participates in osteosarcoma progression through miR-210-5p–mediated suppression, which activates oncogenic autophagy 4. Genome-wide association studies identify PIK3R5 as a novel risk locus for Alzheimer's disease and related dementias 5. Clinical development of multiple PI3K inhibitors—including buparlisib, pictilisib, and gedatolisib—provides pathways to therapeutically target PIK3R5-dependent cancers.