PPP2R5B encodes a regulatory subunit of protein phosphatase 2A (PP2A), a serine/threonine phosphatase that modulates substrate specificity and subcellular localization of PP2A complexes. As a component of the PP2A holoenzyme, PPP2R5B mediates the dephosphorylation and inactivation of AKT1, a central kinase in the PI3K/AKT signaling cascade 1. In insulin-responsive tissues, PPP2R5B expression is elevated during chr11 hyperinsulinemia and contributes to adipocyte insulin resistance by promoting AKT dephosphorylation and reducing glucose uptake 2. De novo mutations clustered in a nine-amino-acid region of PPP2R5B cause human overgrowth syndrome characterized by increased height, macrocephaly, and intellectual disability 1. These mutations are predicted to impair substrate binding and perturb PP2A's ability to dephosphorylate specific substrates. PPP2R5B has been identified as a prognostic biomarker in hepatocellular carcinoma (HCC); elevated expression correlates with worse outcomes and is incorporated into multiple prognostic risk models for HCC prognosis prediction 3456. PPP2R5B knockdown inhibits HCC cell proliferation, suggesting its role in tumor progression 3. No evidence supports a role in familial breast cancer susceptibility 7.