PLEKHA5 (pleckstrin homology domain containing A5) is a cytosolic adaptor protein with dual phosphoinositide-binding capabilities that regulates multiple cellular processes. The protein contains pleckstrin homology (PH) and WW domains 1, with the PH domain specifically binding phosphatidylinositol-3-phosphate, phosphatidylinositol-4-phosphate, phosphatidylinositol-5-phosphate, and phosphatidylinositol-3,5-bisphosphate 1. PLEKHA5 exists as developmentally regulated short and long isoforms, with the long form becoming dominant during brain maturation 1. Mechanistically, PLEKHA5 functions through protein-protein interactions, binding PDZD11 via its WW domain to recruit and target the Menkes ATPase ATP7A to the plasma membrane for copper efflux 2. During mitosis, PLEKHA5 undergoes phosphorylation-controlled relocalization to the plasma membrane, enabling recruitment of functional cargo proteins without exogenous stimuli 3. Disease relevance is substantial across multiple conditions. PLEKHA5 variants associate with acute tubulointerstitial nephritis susceptibility (rs2417771, P=2.14×10⁻⁸) 4. In melanoma, PLEKHA5 promotes malignancy through the TNFα-activated PLEKHA5-FCRLA axis, which disturbs lipid metabolism 5. PLEKHA5 expression correlates with melanoma brain metastasis propensity and promotes blood-brain barrier transmigration 6; conversely, PLEKHA5 acts as a tumor metastasis suppressor in BRCA1-deficient breast cancer 7. PLEKHA5 regulates melanoma proliferation via PI3K/AKT/mTOR signaling and PDCD4 stability 8.