PLEKHH2 is a podocyte-enriched protein with critical roles in glomerular structure and actin dynamics. In the kidney glomerulus, PLEKHH2 functions as a structural linker connecting podocyte foot processes to the glomerular basement membrane through its FERM domain, which mediates direct interactions with focal adhesion proteins like Hic-5 and actin 1. The protein contains a phosphatidylinositol-3-phosphate binding site in its PH1 domain that localizes PLEKHH2 to peripheral cell lamellipodia, where it stabilizes cortical actin by attenuating actin filament depolymerization 1. Beyond renal function, PLEKHH2 acts as an oncogenic driver in non-small cell lung cancer, where elevated expression correlates with poor prognosis and metastasis; its FERM domain binds β-arrestin1 and promotes FAK/PI3K/AKT signaling to enhance cell proliferation and invasion 2. PLEKHH2 is also implicated in genetic susceptibility to diabetic nephropathy, with specific variants associated with disease development 3. Clinically, PLEKHH2 shows reduced expression in focal segmental glomerulosclerosis 1, and PLEKHH2::ALK fusions have been identified in emerging kinase fusion-positive mesenchymal neoplasms, demonstrating responsiveness to ALK inhibitors 4.