Cold Atmospheric Plasma Enhances Fn14 Signaling in Hair Follicle Stem Cells, Thereby Promoting the Healing of Diabetic Skin Wounds in a Mouse Model

The healing of diabetic skin wounds is often delayed due to cellular dysfunction and oxidative stress. Recently, cold atmospheric plasma (CAP) has shown promising efficacy in treating diabetic wounds; however, its exact mechanism remains unclear. The study aimed to investigate the effect of CAP on fibroblast growth factor-inducible 14 (Fn14) signaling-mediated hair follicle stem cell (HFSC) functionality, which may contribute to the healing of diabetic wounds. In vitro experiments were conducted to analyze the effect of CAP treatment on HFSC proliferation, cytokine production, and reactive oxygen species (ROS)-related protein expressions. Animal experiments were performed to verify the effect of CAP treatment on a mouse type 1 diabetic wound model. CAP enhanced both Fn14 expression and HFSC proliferation, accompanied by the activation of the Wnt/β-catenin signaling pathway. Expressions of Sirt1, Nrf2, hypoxia-inducible factor-1α, and Sox9, which were initially suppressed under high glucose conditions, were significantly restored upon CAP stimulation. Moreover, CAP-activated hydrogel promoted diabetic wound healing in this mouse model. Furthermore, inhibition of Fn14 abrogated the promotive effect of CAP intervention. Fn14 signaling is a key mediator, mechanistically linking CAP to HFSC activation and tissue repair. These findings provide a therapeutic blueprint for CAP-based regeneration of diabetic wounds.