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

Area of Science:

• Oncology
• Molecular Biology
• Metabolomics

Background:

• Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality.
• Lenvatinib, a multi-receptor tyrosine kinase (RTK) inhibitor, targets VEGFR/FGFR signaling in HCC.
• This study investigates lenvatinib's impact on the tumor metabolic microenvironment in HCC progression.

Purpose of the Study:

• To explore the mechanisms by which lenvatinib modulates the tumor metabolic microenvironment.
• To elucidate the role of lipid metabolism and specific pathways in lenvatinib's therapeutic effects on HCC.
• To identify potential combination therapies targeting metabolic pathways in HCC.

Main Methods:

• Bioinformatics approaches including metabolic scoring, drug sensitivity analysis, and metabolic profiling.
• In vitro and in vivo functional assays: CCK-8 proliferation, transwell invasion, and scratch wound healing assays.
• Transcriptomic and metabolomic analyses, Western blot, qPCR, immunofluorescence, and co-immunoprecipitation (Co-IP).

Main Results:

• Elevated metabolic pathway activity in HCC correlates with lenvatinib sensitivity.
• Lenvatinib downregulates PLA2G4E and reduces choline and ω-3 arachidonic acid metabolites.
• High PLA2G4E expression predicts poor HCC survival; it promotes tumor growth via the RAS/MAPK/ERK pathway, interacting with MAPK1/3.
• Lenvatinib suppresses MAPK1/3, PLA2G4E, and PDGF/PDGFR; MAPK inhibitors do not affect PDGF/PDGFR.

Conclusions:

• Lenvatinib inhibits HCC by regulating lipid metabolism through the PDGF/GFR-MAPK-PLA2G4E axis.
• This study expands the mechanistic understanding of RTK inhibitors in HCC.
• Findings support the development of metabolic pathway-targeted combination therapies for HCC.