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1000
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Abstract/Summary
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The extensively activated Notch signaling pathway in pancreatic cancer cells is important in carcinogenesis,
chemoresistance, and recurrence. Targeting this pathway is a promising therapeutic strategy for pancreatic cancer;
however, few successful approaches have been reported, and currently used molecular inhibitors of this pathway
exhibit limited clinical benefits. In this study, we identified a previously uncharacterized microprotein, Notch1
degradation-associated regulatory polypeptide (N1DARP), encoded by LINC00261. N1DARP knockout accelerated
tumor progression and enhanced stem cell properties in pancreatic cancer organoids and LSL-Kras, LSL-Trp53, and
Pdx1-Cre (KPC) mice. Mechanistically, N1DARP suppressed canonical and non-canonical Notch1 pathways by
competitively disrupting the interaction between N1ICD and ubiquitin-specific peptidase 10 (USP10), thereby
promoting K11- and K48-linked polyubiquitination of N1ICD. To evaluate the therapeutic potential of N1DARP, we
designed a cell-penetrating stapled peptide, SAH-mAH2-5, with a helical structure similar to that of N1DARP that
confers remarkable physicochemical stability. SAH-mAH2-5 interacted with and promoted the proteasome-mediated
degradation of N1ICD. SAH-mAH2-5 injection provided substantial therapeutic benefits with limited off-target and
systemic adverse effects in Notch1-activated pancreatic cancer models. Taken together, these findings confirm that
N1DARP acts as a tumor suppressor and chemosensitizer by regulating USP10-Notch1 oncogenic signaling, and
suggest a promising therapeutic strategy targeting the N1DARP–N1ICD interaction in Notch1-activated pancreatic
cancer.
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