Nanopuerarin Improves Doxorubicin Therapeutic Efficacy by Inhibiting Angiogenesis via Regulating NSUN2 in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. Doxorubicin (Dox), a conventional chemotherapeutic agent, exhibits unsatisfactory efficacy in HCC due to its poor tumor response, severe cardiotoxicity, and drug resistance. It is urgent to develop strategies to mitigate the side effects and enhance the chemosensitivity of conventional chemotherapy drugs. Traditional Chinese medicine has gained research interest in cancer treatment due to its homology with food and minimal side effects. Puerarin (Pue) has been identified as an effective inhibitor of tumor cell proliferation. However, puerarin's poor water solubility and bioavailability limit its pharmaceutical application. In this study, a novel puerarin nanoparticle (nanoPue) was developed to overcome its limitation. NanoPue could significantly inhibit tumor growth and enhance the chemotherapeutic effect of Dox in HCC models. NanoPue could increase the perivascular coverage within the tumors; decrease the expressions of NSUN2, p-AKT, VEGFA, and MMP-9; and reduce endothelial cell tube formation. In summary, nanoPue improves Dox therapeutic efficacy by decreasing angiogenic factors via regulating NSUN2 in HCC. This study may provide a potential avenue for advancing nanoPue to enhance chemotherapeutic agents in HCC therapy and supply a theoretical support for the clinical application of nanoPue.