Mechanistic study of the role of emodin in targeting and inhibiting the Rap1 signaling pathway to regulate epithelial-mesenchymal transition and reverse cisplatin resistance in hepatocellular carcinoma.

BACKGROUND

Chemotherapy plays a crucial role in the treatment of advanced hepatocellular carcinoma (HCC), but the therapeutic efficacy of cisplatin, a commonly used chemotherapeutic agent, is frequently compromised by drug resistance in advanced stages of the disease. A previous study demonstrated that the combination of emodin and cisplatin alleviates cisplatin resistance by inhibiting epithelial-mesenchymal transition (EMT), but the underlying molecular mechanism remains unclear. This study aimed to systematically elucidate the mechanism of action of emodin in enhancing the antitumor activity of cisplatin.

METHODS

The synergistic concentration of emodin and cisplatin was determined using the CCK-8 assay, combined with transcriptome sequencing to analyze the differentially expressed genes and signaling pathways, and Western blot (WB) to validate the expression of key proteins.

RESULTS

The combination of emodin (50 µM) and cisplatin (10 µM) inhibited the proliferation, invasion, and migration of HepG2 cells. Transcriptomic analysis revealed that the combination exerted a synergistic effect through the regulation of the Rap1 pathway. Pathway inhibition assays verified that the combination downregulated Rap1, vimentin, N-cadherin, and p-AKT/AKT, while upregulating the expression of the epithelial marker E-cadherin.

CONCLUSIONS

Emodin potentiates the anti-tumor efficacy of cisplatin against HCC while suppressing metastasis, mechanistically through targeted inhibition of the Rap1 signaling pathway and subsequent blockade of the EMT.