Abstract Introduction: Deregulation of autophagy in colorectal cancer (CRC) increases cell proliferation, disrupts intestinal epithelial cell homeostasis, and contributes to therapeutic resistance. Therefore, determining the mechanisms by which CRC cells evade autophagy is important for developing new therapeutic strategies. The present study aimed to investigate the role of neuropeptide Y (NPY), a neurohormone that is overexpressed in CRC, and its receptors in regulating CRC cell growth and survival. Methods: The status of NPY and Y1 receptor (Y1R) expressions in CT26 (ATCC) and MC38 (Kerafast) mouse CRC cells was determined by western blot analysis. NPY and Y1R expressions in human colon adenocarcinomas and mouse colon cancer tissues were determined by immunohistochemistry. In vitro cell proliferation assays and flow cytometry were performed to determine the effects of blocking Y1R by antagonist (BIBO3304 trifluoroacetate) or by siRNA-mediated silencing of Y1R in CT26 and MC38 cells. Western blot and qRT-PCR were also performed to determine the changes related to autophagy upon blocking/silencing Y1R. To elucidate the underlying mechanism of Y1R inhibition-induced autophagy, the signaling pathway was analyzed. The impact of the Y1R inhibition on tumor growth and progression was assessed in vivo. Results and Conclusion: Our analysis revealed a significant increase in NPY and Y1R expressions in human colon adenocarcinoma and mouse orthotopic CRC tissues. NPY is primarily secreted by CRC cells that express Y1R on their surfaces. Suppression of Y1R with both an antagonist and siRNA resulted in significant inhibition of proliferation and increased autophagy in CRC cells. Also, the levels of autophagy markers (ATG3, ATG12, ATG16L, LC3A, ATG5, LC3B and BECN1) were significantly enhanced with the inhibition of Y1R. Further analysis revealed that autophagy was induced in CRC cells via AMPK activation, leading to mTOR inhibition. Our results, therefore, indicate that targeting Y1R with clinically safe antagonists may represent a promising therapeutic strategy to suppress tumor growth and restore autophagy-mediated tumor suppression in CRC. These findings suggest a decisive role for the NPY/Y1R axis in regulating CRC cell behavior and indicate the potential of targeting Y1R with clinically safe Y1R inhibitors to improve therapeutic outcomes in CRC. Citation Format: Sooraj Kakkat, Prabhat Suman, Aris Richter, Steven B McClellan, Debanjan Chakroborty, Chandrani Sarkar. Neuropeptide Y Y1 receptor inhibition induces autophagy to limit colorectal cancer progression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4672.
Kakkat et al. (Fri,) studied this question.