STAMBPL1 encodes a zinc metalloprotease that functions as a Lys-63-specific deubiquitinase, playing critical roles in cellular signaling and cancer progression 1. The protein specifically cleaves K63-linked polyubiquitin chains while leaving K48-linked chains intact, positioning it as a key regulator of protein stability and signaling pathways 1. STAMBPL1 acts as a positive regulator of mTORC1 signaling by deubiquitinating SESN2, preventing its interaction with the GATOR2 complex and thereby promoting nutrient-sensing pathways 1. The enzyme regulates multiple oncogenic pathways, including stabilization of EGFR through K63-deubiquitination to prevent lysosomal degradation 2, activation of NF-κB signaling in colorectal cancer 3, and enhancement of JAK2/STAT3 pathways via IQGAP1 stabilization in gastric cancer 4. STAMBPL1 also promotes ferroptosis resistance by stabilizing NRF2 through deubiquitination, creating a positive feedback loop that maintains cellular antioxidant capacity 5. Clinically, STAMBPL1 is overexpressed in multiple cancer types including gastric, colorectal, and breast cancers, where it correlates with poor prognosis and promotes tumor growth, metastasis, and therapy resistance 146. These findings establish STAMBPL1 as a promising therapeutic target for cancer treatment.