Targeting eIF5A2 hypusination with bikinin sensitizes hepatocellular carcinoma to lenvatinib by suppressing TFEB-mediated autophagy.

Authors

Shuqian Wang, Qingyun Zhou, Qiaomei Lin, Shufen Zhang, Ying Cai, Fangnan Wu, Fangyuan Kuang, Lianghui Wang, Shangzhi Xie, Jiahua Lan, Li Zheng, Guodong Xu, Chuxiao Shao, Wei Chen, Chaoyong Tu

Published in

Human cell. Volume 39. Issue 8. Jul 18, 2026. Epub Jul 18, 2026.

Abstract

Hepatocellular carcinoma (HCC) frequently develops resistance to lenvatinib, a multikinase inhibitor, necessitating the development of novel therapeutic strategies. Here, we identify bikinin as a potent eIF5A2 inhibitor through structure-based virtual screening (> 100,000 compounds) and demonstrate its synergistic effect with lenvatinib in HCC cells. Mechanistically, bikinin suppresses deoxyhypusine synthase (DHS)-mediated hypusination of eIF5A2, thereby downregulating the expression of transcription factor EB (TFEB). Furthermore, while DHS knockdown enhanced the sensitivity of HCC cells to lenvatinib, the addition of bikinin treatment provided no further significant sensitization. We also observed that the combination of bikinin and lenvatinib significantly promoted apoptosis and suppressed proliferation in HCC cells. Although TFEB overexpression conferred resistance to lenvatinib and activated autophagy, these effects were reversed by co-treatment with bikinin, which restored lenvatinib sensitivity and inhibited autophagic flux. Bikinin disrupts TFEB-driven autophagy, as evidenced by reduced LC3-II conversion, p62 accumulation, and decreased autophagosome formation. In in vivo experiments, the combination therapy with lenvatinib and bikinin achieved marked tumor regression, accompanied by suppressed Ki-67 expression and elevated TUNEL positivity. Finally, RNA-seq data identified TFEB downregulation as a critical mediator of this therapeutic sensitization. Our work unveils a novel therapeutic axis wherein targeting eIF5A2 hypusination disrupts TFEB-dependent autophagy to overcome lenvatinib resistance in HCC cells.

PMID:
42469533
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.

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