Donepezil promotes skin flap survival through activation of the HIF‐1α/VEGF signalling pathway

Abstract Flaps are mainly used to repair wounds in the clinical setting but can sometimes experience ischaemic necrosis postoperatively. This study investigated whether donepezil, an acetylcholinesterase inhibitor, can enhance the survival rate of flaps. We randomly allocated 36 rats into control, low‐dose (3 mg/kg/day), and high‐dose (5 mg/kg/day) groups. On Postoperative day 7, we assessed flap viability and calculated the mean area of viable flap. After euthanizing the rats, we employed immunological and molecular biology techniques to examine the changes in flap tissue vascularization, apoptosis, autophagy, and inflammation. Donepezil enhanced the expression of hypoxia‐inducible factor and vascular endothelial growth factor to facilitate angiogenesis. In addition, it elevated the expression of LC3B, p62, and beclin to stimulate autophagy. Furthermore, it increased the expression of Bcl‐2 while reducing the expression of Bax, thus inhibiting apoptosis. Finally, it had anti‐inflammatory effects by reducing the levels of IL‐1β, IL‐6, and TNF‐α. The results suggest that donepezil can enhance the viability of randomly generated skin flaps by upregulating HIF‐1α/VEGF signalling pathway, facilitating vascularization, inducing autophagy, suppressing cell apoptosis, and mitigating inflammation within the flap tissue.