Reduced iron in diabetic wounds: An oxidative stress-dependent role for STEAP3 in extracellular matrix deposition and remodelling

Abstract Iron is crucial for maintaining normal bodily function, with well-documented roles in erythropoiesis, haemostasis and inflammation. Despite this, little is known about the temporal regulation of iron during wound healing, nor how iron contributes to wound biology and pathology. Here we profiled tissue iron levels across a healing time-course, identifying iron accumulation during late-stage repair. Interestingly, diabetic murine wounds displayed significantly reduced iron levels, delayed extracellular matrix deposition and dysregulation of iron gene expression. In vitro studies revealed important cellular roles for iron, promoting both deposition and remodelling of extracellular proteins. Functional studies identified oxidative stress-dependent upregulation of the iron-converting metalloreductase, STEAP3, as a key mediator of extracellular matrix production. Taken together, these data reveal a to our knowledge previously unreported mechanistic role for iron in facilitating the remodelling stage of wound healing. Indeed, targeting tissue iron may be a promising future strategy to tackle the development and progression of chronic wounds.