Work

Lenvatinib Promotes Metabolic Reprogramming Through RTK to Inhibit Hepatocellular Carcinoma Proliferation and Metastasis

Year: 2026

Type: article

Abstract: BACKGROUND: Hepatocellular carcinoma (HCC), the third leading cause of cancer mortality, is targeted by Lenvatinib-a multi-receptor tyrosine kinase (RTK) inhibitor suppressing VEGFR/FGFR signaling. This study explored whether lenvatinib modulates the tumor metabolic microenvironment to inhibit HCC progression. METHODS: In this study, we used bioinformatics approaches such as metabolic scoring, drug sensitivity analysis, and metabolic profiling, combined with in vitro and in vivo functional assays including CCK-8 proliferation assays, transwell invasion assays, and scratch wound healing assays to elucidate the novel mechanisms underlying the therapeutic effects of lenvatinib. RESULTS: We identified elevated metabolic pathway activity in HCC tumors, correlating with heightened lenvatinib sensitivity. Transcriptomic analysis revealed downregulation of PLA2G4E post-lenvatinib treatment, while metabolomics showed reduced choline and ω-3 arachidonic acid metabolites. High PLA2G4E expression predicted shorter recurrence-free (RFS) and disease-free survival (DFS). Functional assays demonstrated PLA2G4E's pro-tumor role through interaction with MAPK1/3 in the RAS/MAPK/ERK pathway. Lenvatinib suppressed MAPK1/3, PLA2G4E, and PDGF/PDGFR expression (validated by WB/qPCR/immunofluorescence), whereas MAPK inhibitors did not affect PDGF/PDGFR. Co-IP confirmed PLA2G4E-MAPK1/3 binding. CONCLUSION: These findings establish that lenvatinib inhibits HCC by regulating lipid metabolism through the PDGF/GFR-MAPK-PLA2G4E axis, expanding the mechanistic understanding of RTK inhibitors and proposing metabolic pathway-targeted combination therapies for HCC.

Source: Hepatology Research

DOI: 10.1111/hepr.70164

Authors: Xiaofang Zhao, Shengxiang Yan, Jing Meng, Limin Wang

Institution: Jiamusi University

Language: English

Topic: Hepatocellular Carcinoma Treatment and Prognosis

Subfield: Hepatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,400