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

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.