Combinatorial treatment with donafenib and quercetin suppresses lipid metabolism in HepG2 cells by targeting the CREB1/DRP1/SREBP1 axis

Background: Donafenib (DON) has been found to be effective in prolonging progression-free survival for advanced hepatocellular carcinoma (HCC), although it remains limited in improving long-term survival outcomes. Quercetin (QUE) has also been demonstrated to exhibit anticancer effects in various malignant tumors. The most recent research has shown that the combination therapy of QUE and conventional chemotherapy drugs can enhance its anti-cancer activity. Therefore, this study aimed to investigate whether QUE and DON in combination could synergistically suppress tumor growth in HepG2 cells. Methods: (subcutaneous xenograft models in nude mice) experiments were conducted. The expression of cyclic AMP-responsive element-binding protein 1 (CREB1), a putative common target, was evaluated, and its role in lipid metabolism was investigated. Results: CREB1 was confirmed to be highly expressed in HepG2 cells and serves as a molecular target for both QUE and DON. Suppressing CREB1 expression significantly inhibited lipid metabolism and reduced the biological activity of HepG2 cells. Furthermore, QUE, both alone and in combination with DON, was shown to down-regulate the CREB1/dynamin-related protein 1 (DRP1)/sterol regulatory element-binding protein 1 (SREBP1) signaling axis. This inhibition significantly suppressed lipid metabolism and tumor growth in the nude mouse xenograft models. Conclusions: These findings indicate that the combination of QUE and DON exerts its antitumor effects by inhibiting the CREB1/DRP1/SREBP1 axis mediated lipid metabolism pathway in HepG2 cells. This offers a novel potential approach for enhancing the therapeutic efficacy of DON in the treatment of HCC.