Oncogenic versus tumor-suppressive functions are context-specific.USP1, USP3, USP8, USP21, and USP22 predominantly act as oncogenes by stabilizing pro-tumorigenic substrates (PARP1, PKLR, OGT, HSP90/ENO1, and SIRT1, respectively), whereas USP9X exerts tumor-suppressive activity via EGLN3 stabilization, underscoring the necessity for precision medicine strategies that consider both tumor subtype and USP interactome (Table 1). This evidence concerns the gene PKLR and neoplasm.