Cell proliferation assays and xenograft experiments further supported an antitumor effect of this signaling axis in CRC.<h4>Conclusion</h4>This study suggests that the Gal-3-FBXL5-YAP1 axis plays an important role in restraining CRC progression, expands the mechanistic understanding of Gal-3-associated tumor suppression, and supports Gal-3 as a potential therapeutic target in CRC. Here, LGALS3 is linked to colorectal carcinoma.