Natural product 2-dihydroailanthone suppresses colorectal cancer via targeting integrin α3

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, necessitating the discovery of novel therapeutic agents. Here, we report a natural small molecule, 2-dihydroailanthone (2-DAIL), as a promising candidate for CRC treatment. First, our results demonstrate that 2-DAIL exhibits significant anti-CRC activity in vitro and in vivo. Then, we find that 2-DAIL directly binds to integrin alpha-3 (ITGA3) revealed by stable isotope labeling by amino acids in cell culture coupled with thermal proteome profiling (SILAC-TPP). Additionally, the RNA sequencing data obtained from CRC cells and tumor tissues suggest that 2-DAIL blocks the PI3K/AKT signaling pathway mediated by ITGA3 inhibition. Collectively, 2-DAIL exerts its anti-CRC effects, at least partially, by binding to and inhibiting the function of ITGA3, thereby blocking the activation of the PI3K/AKT signaling pathway, which leads to CRC cell growth inhibition. Our study provides a promising drug candidate for the treatment of CRC and suggests the potential of 2-DAIL in treating other diseases linked to ITGA3 dysfunction.