SREBP2 inhibitor betulin sensitizes hepatocellular carcinoma to lenvatinib by inhibiting the mTOR/IL-1 pathway

Lenvatinib has become the first-line therapy in advanced hepatocellular carcinoma (HCC), but its efficacy is still limited because of the inevitable development of resistance. It has been reported that cellular cholesterol levels are associated with tyrosine kinase inhibitor (TKI) efficacy. Here, we show that betulin, a sterol regulatory element-binding protein 2 (SREBP2) inhibitor, markedly enhances the anti-tumor effect of lenvatinib in HCC both in vitro and in vivo. Our results also show that the combination treatment of lenvatinib and betulin synergistically inhibits the proliferation and clonogenicity of HCC cells. The mRNA and protein expressions of IL-1 beta are markedly decreased in HCC cells treated with betulin, while the sensitivity of HCC cells to lenvatinib is enhanced. Moreover, we find that the knockdown of IL-1 beta also enhances the efficacy of lenvatinib, and recombinant IL-1 beta protein rescues cell viability, which is reduced by lenvatinib in HCC cells. Further mechanistic studies indicate that betulin decreases the level of IL-1 beta in HCC cells by inhibiting the mTOR signaling pathway. Finally, the growth of the tumors in xenograft mouse models subjected to combination treatment is significantly suppressed. In summary, our study reveals that the SREBP2 inhibitor betulin sensitizes hepatocellular carcinoma to lenvatinib by inhibiting the mTOR/IL-1 beta pathway, which may be a promising therapeutic strategy for patients with HCC.