Artemisitene Ameliorates Diabetic Wounds by Inhibiting Ferroptosis Through Activation of the Nrf2/GPX4 Pathway

ABSTRACT Diabetic wounds are hard to heal due to ferroptosis, a specific type of cell death triggered by high blood sugar in human umbilical vein endothelial cells (HUVECs) in the lining of blood vessels. Ferroptosis occurs as a result of excessive iron accumulation and lipid peroxidation. The resulting impairment in endothelial function and tissue scaffolding creates a persistent barrier against effective wound healing. Our study found that artemisitene (ATT), a bioactive compound derived from the herb Artemisia annua , speeded up diabetic wound healing by blocking ferroptosis through the Nrf2 (NFE2 like bZIP transcription factor 2, also known as NRF2: Nuclear factor erythroid 2‐related factor 2)/GPX4 (Glutathione peroxidase 4) pathway. In studies with HG (high glucose)‐damaged HUVECs, treatment with ATT (20 μM) effectively counteracted harmful iron buildup and lipid peroxidation, while also restoring mitochondrial health and reducing the levels of damaging reactive oxygen species (ROS). Computational modeling confirmed that ATT binds tightly to both Nrf2 and GPX4 molecules. Notably, when Nrf2 was blocked, ATT completely lost its protective effect, indicating that Nrf2 is essential for its action. In diabetic rats, applying ATT directly to wounds (20 mg/kg/day) significantly accelerated the rate of wound closure. This treatment worked by triggering two key regenerative processes: stronger new blood vessel growth and better‐organized collagen structure. In practical terms, ATT prevents diabetic wound complications through three connected mechanisms: it uses GPX4 to counteract lipid peroxides, leverages Nrf2 to restore healthy antioxidant balance, and regenerates endothelial cells to drive new blood vessel formation. As the first drug of its kind to target ferroptosis this way, ATT offers a promising multitarget approach for diabetic wounds, tackling the combined problems of oxidative damage, mitochondrial failure, and poor tissue regeneration.