Antitumor efficacy and molecular mechanism of lenvatinib combined with vitamin K2 against hepatocellular carcinoma.

BACKGROUND: This study aimed to investigate the impact of lenvatinib combined with vitamin K2 on hepatocellular carcinoma (HCC) cells and to explore the underlying mechanisms. METHODS: Cell proliferation was assessed via the CCK-8 assay. Cell migration and invasion abilities were evaluated using Transwell assays. Protein and gene expression were analyzed by Western blot and RT-qPCR, respectively. A murine xenograft model was employed to validate the therapeutic effects. RESULTS: The combination of lenvatinib and vitamin K2 more effectively inhibited the proliferation, migration, and invasion of HCC cells compared to monotherapies. Transcriptome analysis identified five commonly altered cell cycle-related genes: OSR2, ETFBKMT, FBXO32 (upregulated) and ATF5, PTPN14 (downregulated). RT-qPCR and Western blot further confirmed that the combination treatment significantly increased the expression of OSR2 and FBXO32 genes and decreased the protein level of PTPN14. Furthermore, functional studies demonstrated that knockdown of OSR2 or FBXO32 attenuated the synergistic anti-proliferative and pro-apoptotic effects of the combination therapy, while overexpression of PTPN14 antagonized this synergistic efficacy, confirming the pivotal roles of these genes in mediating the combined action. Additionally, in vivo experiments showed that the combination treatment significantly inhibited tumor growth in tumor-bearing mice, outperforming either monotherapy. CONCLUSIONS: Lenvatinib combined with vitamin K2 exerts enhanced anti-tumor effects in HCC, likely by modulating key genes including OSR2, FBXO32, and PTPN14. This combination represents a promising therapeutic strategy worthy of further clinical investigation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12957-026-04235-4.