Bikinin sensitizes hepatocellular carcinoma to lenvatinib by suppressing eIF5A2 hypusination and TFEB-mediated autophagy

Despite advances, Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death, and patients frequently develop resistance to standard-of-care treatments like lenvatinib, a multikinase inhibitor. This resistance necessitates novel therapeutic strategies. The eukaryotic initiation factor 5A2 (eIF5A2) and its post-translational modification, hypusination, are implicated in cancer progression. Furthermore, autophagy, a cellular recycling process often mediated by TFEB, can contribute to drug resistance, presenting a critical therapeutic gap.

Researchers identified bikinin as a potent eIF5A2 inhibitor via structure-based virtual screening of >100,000 compounds. They tested its effects alone and in combination with lenvatinib on HCC cell lines, measuring apoptosis, proliferation, and autophagic flux. In vivo, they evaluated combination therapy efficacy in a xenograft model, assessing tumor regression, Ki-67 expression, and TUNEL positivity. RNA-seq was used to identify key mediators of therapeutic sensitization.

Bikinin significantly suppressed DHS-mediated hypusination of eIF5A2, leading to downregulation of TFEB expression. DHS knockdown alone enhanced HCC cell sensitivity to lenvatinib, with bikinin providing no further significant sensitization.

The combination of bikinin and lenvatinib significantly promoted apoptosis and suppressed proliferation in HCC cells, reversing resistance conferred by TFEB overexpression. This combination restored lenvatinib sensitivity and inhibited autophagic flux, evidenced by reduced LC3-II conversion, p62 accumulation, and decreased autophagosome formation. In vivo, combination therapy achieved marked tumor regression, accompanied by suppressed Ki-67 expression and elevated TUNEL positivity. RNA-seq data confirmed TFEB downregulation as a critical mediator.