Narirutin Reprograms Fatty Acid Metabolism and Inhibits Tumorigenesis via Downregulating ADORA3 Expression in Colorectal Cancer.

[OBJECTIVE] The aim of this study is to elucidate the effects and mechanism of narirutin (NR) in colorectal cancer (CRC).

[METHODS] Flow cytometry, xenograft model, cell counting kit-8, colony formation, wound healing, and Transwell assays were performed to assess NR's effects on CRC prevention. Lipid accumulation, triacylglycerol, total cholesterol, and free fatty acids were measured to study NR's effects on fatty acid metabolism in CRC cells. NR's targets and action mechanism in CRC were explored utilizing network pharmacology analysis and molecular docking. Changes in proteins involved in proliferation, apoptosis, epithelial-mesenchymal transition, fatty acid metabolism, and targets were determined via western blot.

[RESULTS] In vitro, NR suppressed CRC cell proliferation, migration, invasion, and fatty acid metabolism but promoted apoptosis. In vivo, NR inhibited tumor growth and reduced the levels of proteins related to proliferation and fatty acid metabolism. Moreover, NR directly targeted adenosine A3 receptor (ADORA3) and inhibited its expression. ADORA3 overexpression attenuated NR's inhibition of cell proliferation, invasion, and fatty acid metabolism.

[CONCLUSION] NR suppressed fatty acid metabolism and malignant biological behaviors of CRC cells, which was involved in the inhibition of ADORA3. This study reveals the anticancer activity of NR in CRC, providing experimental evidence for its further development as an adjuvant therapy or chemopreventive agent for CRC.