Collectively, the results of this study identified N1DARP as a novel tumor suppressor and chemotherapy sensitizer for use in pancreatic cancer therapy by controlling USP10-Notch1 oncogenic signaling and provided insights into a novel strategy that targets USP10–Notch1 interaction by a designed stapled peptide SAH-mAH2-5 derived from the microprotein N1DARP (Supplementary Fig. S11). This evidence concerns the gene NOTCH1 and familial pancreatic carcinoma.