Quercetin enhances skin flap survival via SIRT1-regulated mitophagy promotion and pyroptosis inhibition

  • J Ethnopharmacol. 2026 Jun 12:364:121525. doi: 10.1016/j.jep.2026.121525.
An Wang  1 ,  Sihan Chen  2 ,  Jialong Yang  3 ,  Jiapeng Deng  4 ,  Weilong Song  5 ,  Panshen Xu  6 ,  Hebin Pan  7 ,  Kai Chen  8 ,  Zhigang Bian  9 ,  Wenpin Cai  10 ,  Dingsheng Lin  11
Affiliations
  • 1. Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
  • 2. Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
  • 3. Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
  • 4. Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
  • 5. Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
  • 6. Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
  • 7. Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
  • 8. Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
  • 9. Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
  • 10. Department of TCM Science and Research Center, Wenzhou TCM Hospital of Zhejiang Chinese Medical University, Wenzhou, Zhejiang, China. Electronic address: [email protected].
  • 11. Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
PMID: 41831738 DOI: 10.1016/j.jep.2026.121525
Abstract

Ethnopharmacological relevance: FLAP necrosis remains a prevalent and challenging complication in reconstructive surgery. Quercetin (QUE), a primary bioactive flavonoid found in the traditional Chinese medicine Sophora japonica L. (Huai Hua), is renowned for its abilities to clear heat, cool the blood, and resolve toxicity. Although QUE exhibits a broad spectrum of pharmacological activities, its specific role in FLAP survival remains unclear.

Aim of the study: The purpose of this study was to assess QUE's effectiveness in increasing skin FLAP survival and to clarify underlying mechanisms.

Materials and methods: Use bioinformatics to identify the key mechanisms involved in the IRI process. On the dorsal surface of Sprague-Dawley rats, a modified McFarlane FLAP model was created. The rats were administered control, positive control, QUE-L (50 mg/kg/d), QUE-H (100 mg/kg/d), and QUE-I (QUE + EX527) groups. FLAP survival area, blood perfusion, histopathological changes, oxidative stress markers, LDH release, and the expression of proteins related to inflammation, Pyroptosis, and Mitophagy were evaluated. In vitro experiments were performed in HUVECs subjected to OGD/R, and SIRT1 was further silenced by siRNA to verify the involvement of SIRT1-related signaling pathways.

Results: The bioinformatics analysis indicates that Mitophagy and Pyroptosis are the key pathways regulating the survival of the skin FLAP. QUE treatment significantly improved FLAP survival and blood perfusion. It attenuated oxidative stress, reduced neutrophil infiltration, and downregulated pro-inflammatory cytokines. In vivo experiments showed that QUE suppressed NF-κB/NLRP3-mediated Pyroptosis by activating SIRT1. Concurrently, QUE activated the SIRT1/PINK1/Parkin pathway to enhance Mitophagy. In vitro, QUE exerted similar regulatory effects on pyroptosis- and mitophagy-related proteins in OGD/R-treated HUVECs, whereas SIRT1 knockdown partially abolished these effects, further confirming the essential role of SIRT1 in mediating the protective effects of QUE. These protective effects were also partially reversed by EX527 in vivo.

Conclusion: QUE promotes skin FLAP survival by mitigating Pyroptosis via the SIRT1/NF-κB/NLRP3 pathway, while concurrently enhancing Mitophagy through the SIRT1/PINK1/Parkin axis, thereby offering a novel therapeutic candidate for preventing FLAP necrosis.

Keywords
Ischemia-reperfusion injury; Mitophagy; Pyroptosis; Quercetin; ROS; Skin flap.
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