Bergapten promotes angiogenesis by enhancing endothelial autophagy and reducing pyroptosis in ischemic skin flap

  • Eur J Pharmacol. 2026 Jun 25:1030:179091. doi: 10.1016/j.ejphar.2026.179091.
Xian Liu  1 ,  Jingwei Shi  2 ,  Liang Chen  3 ,  Ningning Yang  4 ,  Yuzhi Zhang  1 ,  Yi Wang  1 ,  Chenhao Ye  1 ,  Yuhang Zhu  5 ,  Liquan An  1 ,  Xuwei Zhu  6 ,  Jian Ding  7
Affiliations
  • 1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China; The Second Clinical Medical College of Wenzhou Medical University, No. 109 WestXueyuan Road, Lucheng District, Wenzhou, 325027, China.
  • 2. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China; Cixi Biomedical Research Institute, Wenzhou Medical University, Ningbo, 315300, China.
  • 3. Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China; The First Clinical Medical College (School of Information and Engineering), Wenzhou Medical University, 325035, China.
  • 4. State Key Laboratory of Macromolecular Drugs and Large-Scale Preparation, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 5. Department of Orthopaedics, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325200, China.
  • 6. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China; The Second Clinical Medical College of Wenzhou Medical University, No. 109 WestXueyuan Road, Lucheng District, Wenzhou, 325027, China. Electronic address: [email protected].
  • 7. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China; The Second Clinical Medical College of Wenzhou Medical University, No. 109 WestXueyuan Road, Lucheng District, Wenzhou, 325027, China. Electronic address: [email protected].
PMID: 42349817 DOI: 10.1016/j.ejphar.2026.179091
Abstract

Background: Necrosis of distal FLAP tissue is often attributed to ischemic injury. Previous research has indicated that Bergapten (BeG), known for its anti-inflammatory and antioxidant activities, protects tissues from ischemic injury. This investigation aimed to ascertain the beneficial effects of BeG on ischemic FLAP survival and explore its underlying mechanisms.

Methods: To assess the survival of ischemic skin flaps, analyses of FLAP viability were conducted utilizing survival rate evaluations and laser Doppler blood flow (LDBF) detection. RNA Sequencing was performed to clarify the underlying molecular processes involved. In addition, angiogenesis, oxidative stress (OS), Pyroptosis, transcription factor EB (TFEB)-mediated Autophagy, and adenosine AMP-activated protein kinase (AMPK)-transient receptor potential mucolipin 1 (TRPML1)-calcineurin (CaN) signaling were assessed using molecular docking (MD), cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR), Western blot (WB) assays, immunofluorescence, and dihydroethidium (DHE) staining.

Results: The improvement in FLAP viability due to BeG was associated with the stimulation of Autophagy, reduction of OS, and inhibition of Pyroptosis. Notably, BeG-mediated enhancement of autophagic flux and increased resistance to OS were crucial for alleviating Pyroptosis in vascular endothelial cells (VECs). BeG promoted Autophagy flux and reduced endothelial oxidative stress by activating TFEB in ischemic flaps. However, the therapeutic effects of BeG were abolished by adeno-associated virus (AAV)-mediated TFEB knockdown. Additionally, BeG regulated TFEB activity through the AMPK-TRPML1-CaN pathway.

Conclusions: BeG enhences Autophagy and alleviates OS through stimulation of the AMPK-TRPML1-CaN-TFEB signaling cascade, hence improving the survival of ischemic flaps and potentially offering significant clinical implications.

Keywords
Autophagy; Bergapten; Ischemic flaps; Oxidative stress; TFEB.
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