HMOX1 drives dihydroartemisinin-sensitized ferroptosis antagonized by mitochondrial fusion

Artemisinin is the key component of artemisinin-based combination therapy (ACT) for malaria. Combinations of artemisinin with partner drugs demonstrate significant therapeutic potential in various diseases, including cancer. However, the precise mechanisms by which artemisinin, in combination with partner drugs, induces cell death are still not fully understood. Ferroptosis, a distinct form of cell death characterized by its dependence on iron, oxygen, and phospholipids (PLs), represents one potential pathway. In this study, we discovered that dihydroartemisinin (DHA), the active metabolite of artemisinin and its derivatives, sensitizes cells to ferroptosis induced by GPX4 inhibition. Through integrated data analysis and experimental validation, we found that DHA enhances ferroptosis sensitivity by promoting heme oxygenase 1 (HMOX1, HO-1)-mediated mitochondrial oxidative stress, thereby triggering a feedback loop that promotes mitochondrial fusion. These results broaden our understanding of the mechanisms of DHA in combination with partner drugs, and provide insights for clinical translation of ferroptosis.