Malaria has been a global epidemic health threat since ancient times. It still claims roughly half a million lives every year in this century. Artemisinin and its derivatives, are frontline antimalarial drugs known for their efficacy and low toxicity. After decades of wide use, artemisinins remain our bulwark against malaria. Here, we review decades of efforts that aim to understand the mechanism of action (MOA) of artemisinins, which help explain the specificity and potency of this anti-malarial drug. We summarize the methods and approaches employed to unravel the MOA of artemisinin over the last three decades, showing how the development of advanced techniques can help provide mechanistic insights and resolve some long-standing questions in the field of artemisinin research. We also provide examples to illustrate how to better repurpose artemisinins for anti-cancer therapies by leveraging on MOA. These examples point out a practical direction to engineer artemisinin for broader applications beyond malaria.

自古以来，疟疾一直是全球流行的健康威胁。在本世纪，它每年仍然夺走大约 50 万人的生命。青蒿素及其衍生物是一线抗疟药物，以其疗效和低毒性而著称。经过几十年的广泛使用，青蒿素仍然是我们对抗疟疾的堡垒。在这里，我们回顾了几十年来旨在了解青蒿素作用机制 (MOA) 的努力，这有助于解释这种抗疟疾药物的特异性和效力。我们总结了过去三十年来用于解开青蒿素 MOA 的方法和方法，展示了先进技术的发展如何有助于提供机制见解并解决青蒿素研究领域的一些长期存在的问题。我们还提供了一些例子来说明如何通过利用 MOA 更好地重新利用青蒿素进行抗癌治疗。这些例子指出了设计青蒿素以实现疟疾以外更广泛应用的实际方向。