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. 2025 Jun 2.
doi: 10.1097/HEP.0000000000001392. Online ahead of print.

The MASTL/YBX1/PAK4 axis regulated by stress-activated STK24 triggers lenvatinib resistance and tumor progression in HCC

Bu-Gang Liang  1 , Yi-Min Zheng  1 , Ming-Hao Xu  1 , Chao Gao  1 , Wen-Xin Xu  1 , Jun-Bo Chen  1 , Si-Wei Wang  2 , Long-Tao Zhao  1 , Guo-Huan Yang  1 , Li Yuan  1 , A-Ying Ma  1 , Ze-Ning Dong  3 , Jia-Bin Cai  1 , Hui-Chuan Sun  1 , Ai-Wu Ke  1 , Ying-Hao Shen  1
Affiliations

The MASTL/YBX1/PAK4 axis regulated by stress-activated STK24 triggers lenvatinib resistance and tumor progression in HCC

Bu-Gang Liang et al. Hepatology. .

Abstract

Background and aims: Many patients with HCC present inadequate responses to lenvatinib therapy. Therefore, it is important to elucidate the underlying mechanisms of resistance and to formulate effective reversal strategies.

Approach and results: We conducted transcriptome and proteome sequencing analyses of lenvatinib-resistant cell lines and patient-derived tissues, identifying microtubule-associated serine/threonine kinase-like (MASTL) as a critical factor associated with lenvatinib resistance in HCC. Then, we utilized subcutaneous mouse models, half maximal inhibitory concentration (IC 50 ) measurements, and colony formation assays to determine the biological function of MASTL in promoting tumor growth and mediating resistance to lenvatinib. To further elucidate the underlying mechanisms, we performed co-immunoprecipitation and mass spectrometry analyses, revealing that MASTL facilitates the phosphorylation of Y-box binding protein-1 (YBX1). Using chromatin immunoprecipitation assays, we subsequently confirmed that phosphorylated YBX1 transcriptionally activates PAK4, identifying PAK4 as a downstream effector of the MASTL pathway. Moreover, mass spectrometry and phosphorylation analysis indicated that serine/threonine protein kinase 24 (STK24), a stress-responsive kinase, can activate MASTL in HCC under lenvatinib exposure. Notably, disruption of the MASTL/YBX1/PAK4 signaling axis restored HCC sensitivity to lenvatinib.

Conclusions: We propose that the MASTL/YBX1/PAK4 axis, which is activated by stress-induced STK24, plays a crucial role in lenvatinib resistance. Inhibiting this axis by targeting MASTL effectively overcomes lenvatinib resistance in HCC.

Keywords: HCC; MASTL; combination therapy; lenvatinib resistance; phosphorylation modification.

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