PTEN-Long-mediated molecular therapy: current evidences and future perspectives.

PTEN-Long (PTEN-L) is a translational variant of the tumor suppressor PTEN, characterized by a unique N-terminal 173-amino acid extension that confers its secreted and membrane-permeable properties. As a constitutively active phosphatase, PTEN-L retains core lipid phosphatase activity to antagonize the PI3K/Akt/mTOR pathway and regulates PINK1/Parkin-mediated mitophagy via its protein phosphatase function. It participates in diverse pathophysiological processes, acting as a tumor suppressor in non-small cell lung cancer, glioblastoma, and so on, while exerting protective effects in metabolic and fibrotic diseases. Its distinctive intercellular trafficking ability has facilitated the development of innovative molecular therapies, including engineered oncolytic viruses and cell-mediated delivery systems, with promising preclinical anti-tumor efficacy. This review summarizes PTEN-L's structural features, core functions, and roles in diseases, highlights progress in PTEN-L-mediated therapy, and prospects its clinical translation potential, providing a basis for precision medicine in PTEN-abnormal diseases.