YAP promotes the healing of ischemic wounds by reducing ferroptosis in skin fibroblasts through inhibition of ferritinophagy
Guoqi Cao,
Siyuan Yin,
Jiaxu Ma,
Yongpan Lu,
Ru Song,
Zhenjie Wu,
Chunyan Liu,
Jian Liu,
Peng Wu,
Rui Sun,
Aoyu Chen,
Yibing Wang
Affiliations
Guoqi Cao
Department of Plastic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250012, PR China; Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China
Siyuan Yin
Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China; Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, 250014, PR China
Jiaxu Ma
Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China; Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, 250014, PR China
Yongpan Lu
Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China; Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, 250014, PR China
Ru Song
Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China; Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, 250014, PR China
Zhenjie Wu
Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China; Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, 250014, PR China
Chunyan Liu
Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China; Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, 250014, PR China
Jian Liu
Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China; Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, 250014, PR China
Peng Wu
Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China; Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, 250014, PR China
Rui Sun
Department of Plastic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250012, PR China; Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China
Aoyu Chen
Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China; Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, 250014, PR China
Yibing Wang
Department of Plastic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250012, PR China; Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, Jinan, Shandong, 250014, PR China; Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, 250014, PR China; Corresponding author. Department of Plastic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250012, PR China.
The impaired healing of chronic wounds is often attributed to the ischemic and hypoxic microenvironment, leading to increased cell death. Ferroptosis, a novel form of cell death unveiled in recent years, could potentially be linked with the process of wound healing. In this study, we explored the significance and mechanism of ferroptosis in ischemic wounds. Using transmission electron microscopy, Western blot, flow cytometry, immunofluorescence, and glutathione (GSH) assay, we observed that the death of primary mouse skin fibroblasts induced by oxygen and glucose deprivation (OGD) was associated with ferroptosis. Specifically, we observed elevated intracellular Fe2+ and lipid peroxidation levels and decreased GSH levels in vitro, indicative of ferroptosis. Importantly, we found that ferroptosis in OGD-treated skin fibroblasts was dependent on autophagy, as the autophagy inhibitor chloroquine phosphate (CHQ) significantly reduced ferroptosis induced by OGD. Moreover, our study revealed that NCOA4-mediated ferritinophagy significantly contributed to the occurrence of ferroptosis induced by OGD in skin fibroblasts. Additionally, we identified the involvement of YAP in the regulation of ferritinophagy, with YAP suppressing NCOA4 expression in OGD-treated skin fibroblasts, thereby reducing ferroptosis. Furthermore, in ischemic wound models in mice, both inhibitors of ferroptosis and autophagy promoted wound healing, while a YAP inhibitor, verteporfin, delayed wound healing. In conclusion, these findings indicate that ferroptosis, regulated by YAP through ferritinophagy inhibition, presents a novel mechanism responsible for the delayed healing of ischemic wounds. Understanding this process could offer promising therapeutic targets to improve wound healing in ischemic conditions.
