UPF1 promotes wound healing in diabetic foot ulcer by reducing CYP1A1-induced oxidative stress through enhancing EGR1 degradation.
Diabetic foot ulcer (DFU) is a severe and debilitating complication of diabetes with limited effective therapeutic strategies, and persistent oxidative stress and inflammation are the core pathological factors leading to its impaired wound healing. RNA-binding protein UP frameshift 1 (UPF1) is implicated in modulating oxidative stress pathways, yet its regulatory role and underlying mechanism in DFU-associated oxidative stress remain largely unelucidated. This study aims to explore the function of UPF1 in oxidative stress during DFU pathogenesis and identify its related molecular regulatory axis, so as to provide novel therapeutic targets for DFU management. Human dermal fibroblasts (HDFs) were exposed to 30 mM high glucose (HG) to simulate diabetic conditions. The results showed that HG stimulation increased cytochrome P450 family 1 subfamily A member 1 (CYP1A1) and early growth response 1 (EGR1) expression, exacerbating oxidative stress and inflammation in HDFs. EGR1 knockdown or CYP1A1 inhibition attenuated these effects. Mechanistically, EGR1 transcriptionally activated CYP1A1, while UPF1 bound to and destabilized EGR1 mRNA. As expected, UPF1 upregulation rescued HG-induced inflammation and oxidative stress in HDFs, whereas concurrent EGR1 overexpression abolished this protective effect. In conclusion, UPF1 exerts a protective role in HG-stressed HDFs by degrading EGR1 mRNA, which in turn suppresses the transcriptional activation of CYP1A1 and subsequent CYP1A1-mediated oxidative stress and inflammation, thus uncovering a novel UPF1-EGR1-CYP1A1 regulatory axis in DFU pathogenesis. These core findings not only enrich the molecular understanding of oxidative stress regulation in DFU but also provide promising novel therapeutic targets for DFU management.