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

  • J Pharm Anal. 2025 Dec;15(12):101333. doi: 10.1016/j.jpha.2025.101333.
Xin-Meng Zhou  1 ,  Ying Yang  1 ,  Dao-Jiang Yu  1  2 ,  Teng Xie  1 ,  Xi-Lu Sun  1 ,  Ying-Xuan Han  1 ,  Hai-Ying Tian  1 ,  Qing-Qing Liao  1 ,  Yu-Jie Zhao  3 ,  Yih-Cherng Liou  4 ,  Wei Huang  5  6 ,  Yong Xu  5  6 ,  Xi Kuang  1 ,  Xiao-Dong Sun  1  3  7 ,  Yuan-Yuan Zhang  1  7
Affiliations
  • 1. Department of Pharmacology, West China School of Pharmacy, West China School of Basic Medical Sciences & Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610041, China.
  • 2. Department of Plastic Surgery, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China.
  • 3. Medical College, Tibet University, Lhasa, 850000, China.
  • 4. Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore.
  • 5. Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
  • 6. Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, Sichuan, 646000, China.
  • 7. Tianfu Jincheng Laboratory, Chengdu, 610093, China.
PMID: 41487142 DOI: 10.1016/j.jpha.2025.101333
Abstract

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 (WT) 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 (Parkin/PRKN/Prkn). 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 (Prkn -/-) DFU mice. Inhibition of NAR binding to estrogen receptors (ERs) using tamoxifen (TAM) 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 (CETSA) revealed that NAR specifically bound to 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.

Keywords
Diabetic foot ulcer; E3 ubiquitin-protein ligase parkin; Estrogen receptor α; Mitochondrial quality control; Mitophagy; Naringenin.
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