Neutrophil extracellular traps induce fibroblast ferroptosis via IRE1α/XBP1-mediated ER stress to impair diabetic wound healing.

Delayed wound healing in diabetes markedly increases the risk of amputation and systemic infection. However, the underlying molecular mechanisms are unclear. Fibroblasts are essential in wound repair through collagen secretion, and their dysfunction severely impairs wound healing and tissue regeneration. Increasing evidence indicates that excessive production of neutrophil extracellular traps (NETs) exacerbates local inflammation and induces cell death, thereby delaying wound healing. Despite these findings, the precise mechanisms underlying NETs-induced impairment of wound healing remain poorly understood. This study utilized in vitro and in vivo models to examine the molecular mechanisms by which NETs facilitate fibroblast ferroptosis through endoplasmic reticulum (ER) stress and contribute to impaired diabetic wound healing. Our findings demonstrate that NETs induce ferroptosis in fibroblasts, thus impairing their collagen secretion capacity. We further demonstrate that IRE1α/XBP1, a key ER stress pathway, participates in NETs-induced ferroptosis in fibroblasts. Furthermore, targeting this pathway markedly improved diabetic wound healing. These findings highlight a novel molecular target and potential therapeutic strategy for the treatment of treating refractory diabetic wounds.