Cucurbitacin I exerts its anticancer effects by inducing cell cycle arrest via the KAT2a-ube2C/E2F1 pathway and inhibiting HepG2-induced macrophage M2 polarization.

Hepatocellular carcinoma (HCC) is one of the most common malignancies globally, particularly prevalent in China, where it accounts for nearly half of the world's new cases and deaths each year, but has limited therapeutic options. This study systematically investigated the impact of cucurbitacin I on HCC cell lines including SK-Hep-1, Huh-7, and HepG2. The results revealed that cucurbitacin I not only inhibited cell proliferation, cell migration and colony formation, but also induced apoptosis in HCC cells. The apoptotic induction was accompanied by a decrease in the expression of the anti-apoptotic factor B-cell lymphoma 2 (Bcl2), and an elevation in the expression levels of pro-apoptotic factors, including tumor protein p53 (P53), bcl2 associated X-apoptosis regulator (Bax), and caspase3 (Cas3). Additionally, cucurbitacin I caused cell cycle arrest by modulating the lysine acetyltransferase 2A (KAT2A)-E2F transcription factor 1 (E2F1)/Ubiquitin-conjugating enzyme E2 C (UBE2C) signaling axis. In terms of regulation on tumor microenvironment, cucurbitacin I was demonstrated the ability to inhibit HCC cell-induced M2 polarization of macrophages. This comprehensive study unveils the multifaceted anti-cancer mechanisms of cucurbitacin I, providing robust support for its potential application in the treatment of HCC, offering new avenues for the future development of HCC treatment strategies.