双氢青蒿素在肿瘤治疗中的应用及分子机制 研究进展

Advances of Dihydroartemisinin in Cancer Therapy and Molecular Mechanisms

摘要: 双氢青蒿素(Dihydroartemisinin, DHA)是青蒿素的主要活性代谢产物，作为一线抗疟药物在临床广泛应用。近年来大量研究证实，DHA对多种恶性肿瘤具有显著的抗肿瘤活性，且对正常细胞毒性较低，展现出良好的抗肿瘤药物前景。DHA可以通过不同途径发挥抗肿瘤作用，主要包括诱导铁死亡与凋亡、调控自噬、阻滞细胞周期、抑制迁移侵袭和血管生成、调节肿瘤免疫微环境，以及靶向多条关键信号通路如Ras、STAT3、PI3K/AKT/mTOR和NF-κB等。此外，DHA与传统化疗药物或靶向药物联用可产生协同作用，并逆转肿瘤耐药。然而，DHA也具有如水溶性差、生物利用度低等药代动力学方面的局限性，亟待新型纳米给药系统的开发。本文系统综述了DHA在肿瘤治疗中的主要作用机制和联合用药策略的研究进展，并探讨了其临床转化面临的机遇与挑战，以期为DHA的深入研究和临床抗肿瘤治疗的应用提供理论参考。

Abstract: Dihydroartemisinin (DHA) is the main active metabolite of artemisinin and is widely used in clinical practice as a first-line antimalarial drug. In recent years, a growing body of research has validated the significant antitumor activity of DHA against various malignancies, accompanied by low toxicity to normal cells, positioning it as a promising candidate for drug repurposing in oncology. This review aims to systematically summarize the antitumor mechanisms of DHA and its therapeutic strategies. The analysis reveals that DHA’s anticancer effects are multifaceted, primarily involving the induction of ferroptosis and apoptosis, regulation of autophagy, cell cycle arrest, inhibition of migration, invasion, and angiogenesis, modulation of the tumor immune microenvironment, and targeting of key signaling pathways such as Ras, STAT3, and PI3K/AKT/mTOR. Furthermore, DHA demonstrates synergistic effects with conventional chemotherapeutic and targeted agents, effectively reversing drug resistance. The pharmacokinetic limitations of DHA, including poor aqueous solubility and low bioavailability, have driven the development of novel nano-delivery systems. In conclusion, the profound anticancer potential of DHA is substantiated by these mechanisms, though further exploration is needed to address its clinical translation, including pharmacokinetic optimization and large-scale clinical validation. These findings provide a valuable reference for future research and the clinical application of DHA as an anticancer agent.