PPM1E is a metal-dependent serine/threonine protein phosphatase that belongs to the PP2C phosphatase family and requires Mn2+/Mg2+ ions for catalytic activity 1. The enzyme functions as a critical negative regulator of AMPK signaling by dephosphorylating AMPKα at threonine-172, thereby inactivating this key metabolic kinase 23. PPM1E also regulates calcium/calmodulin-dependent protein kinases (CaMKs) and other kinases involved in cellular signaling pathways 4. The phosphatase plays important roles in multiple cellular processes including cell proliferation, metabolic regulation, and stress responses. In disease contexts, PPM1E expression is frequently dysregulated: it is upregulated in gastric cancer and osteoblastoma, where its AMPK-inhibiting activity promotes tumor cell proliferation 23. Conversely, PPM1E expression is reduced in type 2 diabetes pancreatic β-cells, which may represent a compensatory mechanism to maintain insulin secretion through sustained AMPK activation 5. PPM1E is subject to post-transcriptional regulation by microRNA-135b-5p, which can silence PPM1E expression to activate AMPK signaling and provide cellular protection against various stresses 67. These findings suggest PPM1E represents a potential therapeutic target for metabolic diseases and cancer.