Naringenin boosts Parkin-mediated mitophagy via estrogen receptor alpha to maintain mitochondrial quality control and heal diabetic foot ulcer

Diabetic foot ulcer (DFU) is an increasing global burden due to the rising prevalence of diabetes, and no specific pharmacological targets or satisfactory drugs are currently available for this devastating ailment. In this study, naringenin (NAR) was found to accelerate diabetic wound healing in diabetic C57BL/6J wild-type mice by reducing oxidative stress, as assessed through histological assay. NAR also alleviated the inhibition of proliferation, inflammation, cell senescence, and apoptosis in HaCaT cells induced by high glucose (HG). Mechanistically, the beneficial effects of NAR on wound healing are dependent on the E3 ubiquitin-protein ligase parkin. NAR upregulated the expression level of Parkin and promoted its mitochondrial translocation, thereby activating Parkin-mediated mitophagy and maintaining mitochondrial quality control (MQC). Moreover, the wound healing-promoting effects of NAR were significantly diminished in Parkin knockdown HaCaT cells and Prkn knockout DFU mice. Inhibition of NAR binding to estrogen receptors (ERs) using tamoxifen abolished the protective effects of NAR in HG-induced HaCaT cells. The luciferase reporter assay confirmed that NAR enhanced ERs binding to the estrogen response element (ERE), thereby upregulating Parkin transcription. Additionally, the cellular thermal shift assay revealed that NAR specifically bound to estrogen receptor alpha (ERα). In conclusion, NAR promoted DFU wound healing by enhancing Parkin-mediated mitophagy via binding to ERα, highlighting its potential as a promising therapeutic candidate.