USP22 and neoplasm: Targeting the USP22–SIRT1 axis therefore offers a novel precision strategy for CCA: (1) developing small-molecule USP22 inhibitors or shRNA/CRISPR-mediated gene silencing to block SIRT1 stabilization, and (2) combining SIRT1 inhibitors (e.g., EX-527, Selisistat) or epigenetic drugs to achieve synergistic anti-tumor effects in USP22high/SIRT1high patients.