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.