STAMBPL1 is a zinc metalloprotease that catalyzes Lys-63-linked deubiquitination, removing K63-linked polyubiquitin chains from client proteins while leaving Lys-48-linked chains intact. It acts as a positive regulator of mTORC1 signaling by deubiquitinating SESN2, thereby disrupting SESN2 interaction with the GATOR2 complex, and coordinates cellular metabolism with nutrient availability, particularly leucine sensing 1. Beyond mTOR regulation, STAMBPL1 functions in multiple cancer contexts: it stabilizes AXL to promote mesenchymal phenotype and immune evasion in renal cell carcinoma 2, stabilizes NRF2 to suppress ferroptosis in cholangiocarcinoma 3, maintains EGFR protein and mRNA levels in hepatocellular carcinoma 4, promotes angiogenesis in triple-negative breast cancer via HIF1α upregulation 5, and stabilizes IQGAP1 to activate JAK2/STAT3 signaling in gastric cancer 6. In colorectal cancer, STAMBPL1 overexpression drives proliferation and metastasis through NF-κB pathway activation 7. Therapeutically, STAMBPL1 inhibition shows promise: blocking the STAMBPL1–Sestrin2 interaction inhibits mTORC1 1, liquidambaric acid disrupts the STAMBPL1/NRF2 feedback loop 3, and STAMBPL1 suppression synergizes with PD-1 blockade in renal cancer and lenvatinib in hepatocellular carcinoma 24.