What question did this study set out to answer?

The study investigates how CDK4 influences lenvatinib resistance in hepatocellular carcinoma and evaluates luteolin's potential to counteract this resistance.

April 12, 2026Open Access

CDK4 inhibition by luteolin enhances lenvatinib sensitivity in HCC via Wnt/β-catenin modulation

Key Points

The study investigates how CDK4 influences lenvatinib resistance in hepatocellular carcinoma and evaluates luteolin's potential to counteract this resistance.
Utilized bioinformatics to identify CDK4 as a target in resistant HCC
Conducted in vitro assays to assess the effects of Danshen and luteolin on cell viability and apoptosis
Performed in vivo xenograft studies to evaluate tumor growth suppression
Tested Wnt/β-catenin pathway using inhibitors and luciferase reporter assays
Identified high CDK4 levels correlate with poor prognosis and lenvatinib resistance
Luteolin and Danshen reduced CDK4 protein levels, enhancing sensitivity to lenvatinib
Luteolin facilitated CDK4 degradation through the ubiquitin-proteasome pathway
Modulation of Wnt/β-catenin signaling was significant in enhancing lenvatinib sensitivity

Abstract

Hepatocellular carcinoma (HCC) frequently develops resistance to lenvatinib. We investigated CDK4’s role in this resistance and the potential of Danshen/luteolin to overcome it. Using bioinformatics, in vitro models, and in vivo xenografts, we modulated CDK4 expression (overexpression/shRNA) in HCC cells. Danshen extract and luteolin’s effects on lenvatinib sensitivity were assessed via viability/apoptosis assays and molecular analyses. Wnt/β-catenin pathway involvement was tested with an inhibitor and luciferase reporter. Network pharmacology identified CDK4 as a Danshen target in resistant HCC. High CDK4 correlated with poor prognosis and increased resistance. Danshen/luteolin reduced CDK4 protein, enhanced lenvatinib sensitivity, and suppressed tumor growth in vitro and in vivo. Luteolin promoted CDK4 degradation via the ubiquitin-proteasome pathway and modulated Wnt/β-catenin signaling, crucial for resistance. CDK4 is a key mediator of lenvatinib resistance in HCC. Danshen-derived luteolin acts as a CDK4 inhibitor, enhancing lenvatinib sensitivity by degrading CDK4 and targeting Wnt/β-catenin, supporting combination therapies to overcome resistance.

Bookmark

View Full Paper