Activating Ferroptosis of M1 Macrophages: A Novel Mechanism of Asiaticoside Encapsuled in GelMA for Anti-Inflammation in Diabetic Wounds.

Diabetic wounds are characterized by chronic inflammation, partly due to the persistent accumulation of pro-inflammatory M1 macrophages. Asiaticoside (AS), a triterpenoid extracted from Centella asiatica, has known anti-inflammatory effects in several diseases, but the underlying mechanisms in diabetic wounds are still unclear. This study reveals that AS alleviates inflammation in diabetic wounds by activating ferroptosis of M1 macrophages. In vitro, AS reduces the number of M1 macrophages in a high glucose microenvironment and their secretion of proinflammatory cytokines with concurrent induction of ferroptosis. Further investigation shows that AS-activated ferroptosis is attributed to the downregulation of ferroportin 1 (FPN1) and ferritinophagy-induced degradation of ferritin heavy chain 1 (FTH1), which together increase the amount of intracellular free ferrous ions (Fe(2+)). In vivo, AS-encapsulated gelatin-methacryloyl hydrogels accelerates diabetic wound healing and shortens the inflammatory period by activating ferroptosis of M1 macrophages with the reduced expression of FPN1 and FTH1. These results suggest a promising AS-based strategy for treating inflammatory diseases associated with excessive activation of M1 macrophages.