Our findings revealed that α-hederin served as a potential therapeutic candidate for the prevention and treatment of CRC by suppressing STAT3 activation mainly through targeting and decreasing USP5 expression and inhibiting the deubiquitylation of STAT3 mediated by USP5, promoting STAT3 ubiquitin-proteasome degradation, and thereby reducing the inflammatory response and halting the proliferation of malignant IECs, providing a promising therapeutic strategy for CRC prevention and treatment (Fig. 11). The gene discussed is STAT3; the disease is colorectal carcinoma.