Roxadustat: A catalyst for diabetic wound healing through re-epithelialization and angiogenesis

Hypoxia-inducible factor 1 (HIF-1) signaling mediates multiple links of wound healing. Tissue hypoxia and dysregulation of HIF-1 signal play a crucial role in non-healing diabetic wounds. Previous studies have found that roxadustat (FG-4592) can promote epidermal stem cell proliferation by upregulating the HIF signaling pathway. This study aimed to investigate the role of roxadustat in the wound healing of diabetic mice.

The study was divided into in vivo and in vitro experiments. In the in vivo experiment, mice were categorized into three groups: control group, diabetes group, and diabetes + roxadustat group. Diabetic mice were injected intraperitoneally with roxadustat daily at a dose of 10 mg/kg. Hematoxylin & eosin staining and Masson staining were employed to assess wound healing speed and quality. Immunohistochemical staining was used to detect HIF-1a and proliferating cell nuclear antigens. Western blot was conducted to examine markers associated with Notch1 signaling pathway activation (Notch Intracellular Domain [NICD]), keratinocyte differentiation, and angiogenesis. In the in vitro experiment, HaCaT cells were divided into control (Glu 5.5 mM), high-glucose (Glu 30 mM), and high-glucose + drug (Glu 30 mM + FG-4592) groups, with a treatment concentration of FG-4592 set at 10 µM. Following 48 h of treatment period, protein was extracted for co-immunoprecipitation analysis to determine the interaction between HIF-1a and NICD, and fluorescence staining was conducted to assess their co-localization.

Roxadustat reversed the slow wound healing caused by diabetes and significantly improved the quality of healing (P < 0.05). It upregulated the inhibited HIF-1 signaling in diabetic mice (P < 0.05) and triggered cell proliferation. It downregulated the hyperactivated Notch1 signaling in diabetic mice (P < 0.05) and induced keratinocyte dedifferentiation, which were both responsible for wound re-epithelialization. Roxadustat also reversed the downregulated expression of vascular endothelial growth factor and CD31 in diabetic mice (P < 0.05) and accelerated the wound angiogenesis process.

Roxadustat shows potential as a therapeutic drug by promoting re-epithelialization and angiogenesis to bring vigor to the impaired diabetic wound.