PHLPP2 is a member of the metal-dependent protein phosphatase (PPM) family involved in regulating Akt and PKC signaling 1. However, recent structural analysis reveals that PHLPP2 is a pseudophosphatase that lost catalytic activity in the metazoan ancestor, containing a single zinc ion in its catalytic center but lacking enzymatic activity in vitro 2. Despite this surprising finding, PHLPP2 retains functional importance through noncatalytic mechanisms, potentially serving a scaffolding role on membranes 2. In disease contexts, PHLPP2 functions as a tumor suppressor through the PI3K-AKT pathway regulation. CircANAPC7 suppresses pancreatic cancer growth and cachexia by acting as a miR-373 sponge to maintain PHLPP2 expression, which dephosphorylates AKT and inhibits proliferation 3. In hepatocellular carcinoma, TRIM22-mediated PHLPP2 degradation activates AKT-p53-p21 signaling and induces cellular senescence 4. Conversely, downregulation of PHLPP2 by exosomal miR-25-3p in gliomas and miR-188-3p in colorectal cancer promotes tumor progression by activating PI3K-AKT-mTOR signaling 56. In cardiac tissue, METTL14-mediated suppression of Phlpp2 m6A modification activates AKT-S473, promoting physiological hypertrophy and protecting against ischemia-reperfusion injury 7. Genetic polymorphisms in PHLPP2 (rs61733127) are associated with increased colon cancer susceptibility 8.