Rosmarinic acid combined with cisplatin induces proliferation inhibition of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is characterized by high proliferation and metastasis potential and is prone to chemotherapy resistance, which seriously restricts the clinical efficacy of cisplatin (DDP)-based treatment. Rosmarinic acid (RA) is a natural bioactive compound that has shown potential anti-tumor and chemosensitizing effects in preclinical studies. The purpose of this study was to systematically explore the synergistic anti-hepatocellular carcinoma mechanism of RA combined with DDP through network pharmacology, molecular docking, molecular dynamics simulation, and in vitro experimental verification. Network pharmacology analysis identified HCC-related core targets, which were enriched in cell cycle, apoptosis, and tumor metastasis pathways. Molecular simulation results confirmed that both RA and DDP can stably bind to core oncogenic proteins and exhibit good structural stability. In vitro experiments demonstrated that the combination of RA/DDP had a significant time-and dose-dependent inhibitory effect on the proliferation and colony formation of HCC cells. This combination significantly induced cell cycle arrest and apoptosis in Huh-7 cells and inhibited their migration and invasion, outperforming the single-drug groups. This study provides an integrated and preliminary mechanistic exploration of the potential synergistic effects of RA and DDP against HCC, integrating network pharmacology, molecular simulations, and in vitro functional assays. These in vitro findings suggest that RA may enhance DDP sensitivity in HCC cell models. Further in vivo and clinical studies are needed to determine whether RA can serve as a DDP-sensitizing agent and whether these effects translate into clinical benefit in HCC.