PPME1 (protein phosphatase methylesterase 1) is a PP2A-specific demethylase that negatively regulates protein phosphatase 2A by removing methyl groups from its catalytic subunit at leucine 309, thereby inactivating the enzyme 1. This demethylation activity occurs at the carboxy-terminal region and displaces manganese ions essential for PP2A function 1. PPME1 expression is frequently elevated in multiple cancer types through gene amplification or regulatory pathways. In gastric and lung cancers, PPME1 amplification (3-4% of samples) correlates with increased protein expression and poor prognosis; knockdown of PPME1 inhibits cell proliferation and induces apoptosis through decreased ERK and AKT phosphorylation 1. Similarly, PPME1 promotes migration and invasion in choriocarcinoma cells as an effector of the oncofetal protein IMP1 2. In pancreatic cancer, PPME1 expression is elevated through circRNA and lncRNA regulatory axes, promoting tumor growth and angiogenesis 34. Unexpectedly, PPME1 expression predicts favorable clinical outcomes in colorectal cancer, suggesting cancer-type-specific functions 5. Beyond cancer, PPME1 participates in glucose-deprivation-induced cell death through PP2A demethylation and RIPK1 activation 6, and its dysregulation contributes to PP2A inactivation in Alzheimer's disease and vascular dementia 7.