2. Academic Validation
  3. Flufenamic acid inhibits pyroptosis in ischemic flaps via the AMPK-TRPML1-Calcineurin signaling pathway

Flufenamic acid inhibits pyroptosis in ischemic flaps via the AMPK-TRPML1-Calcineurin signaling pathway

  • Burns Trauma. 2025 Feb 17:13:tkaf007. doi: 10.1093/burnst/tkaf007.
Liang Chen 1 2 3,  Ningning Yang 1 2 3,  Kongbin Chen 1 2 3,  Yingying Huang 1 2 3,  Xian Liu 1 2 3,  Gaoxiang Yu 4,  Fulin Wang 1 2 3,  Yong Gou 1 2 3,  Yi Wang 1 2 3,  Xiaolang Lu 1,  Yuqi Wang 5,  Lipeng Zhu 6,  Weiyang Gao 1 2 3,  Jian Ding 1 2 3
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No. 109 WestXueyuan Road, Lucheng District, Wenzhou 325027, China.
  • 2 Zhejiang Provincial Key Laboratory of Orthopaedics, No. 109 WestXueyuan Road, Lucheng District, Wenzhou 325027, China.
  • 3 The Second Clinical Medical College of Wenzhou Medical University, No. 109 WestXueyuan Road, Lucheng District, Wenzhou 325027, China.
  • 4 Department of Hand Surgery, Ningbo Sixth Hospital, No. 1059 Zhongshan East Road, Jiangdong District, Ningbo 315042, China.
  • 5 School of nursing, Wenzhou medical university, No. 109 WestXueyuan Road, Lucheng District, Wenzhou 325027, China.
  • 6 The Fifth Affiliated Hospital of Zhengzhou University, No. 3 Kangfu Front Street, Zhengzhou 450015, China.
PMID: 40655077 DOI: 10.1093/burnst/tkaf007
Abstract

Background: Ischemic injury is a primary cause of distal FLAP necrosis. Previous studies have shown that Flufenamic acid (FFA) can reduce inflammation, decrease oxidative stress (OS), and promote angiogenesis, suggesting its potential role in protecting flaps from ischemic damage. This study investigated the effects and mechanisms of FFA in enhancing the survival of ischemic flaps.

Methods: The viability of ischemic flaps was evaluated using laser doppler blood flow (LDBF) and survival rates. We examined levels of Pyroptosis, OS, transcription factor E3 (TFE3)-induced Autophagy, and elements of the AMPK-TRPML1-Calcineurin pathway through western blotting (WB), immunofluorescence, molecular docking, cellular thermal shift assay (CETSA) and surface plasmon resonance.

Results: The findings suggest that FFA significantly enhances the viability of ischemic flaps. The improvement in FLAP survival associated with FFA can be attributed to increased Autophagy, diminished OS, and the suppression of Pyroptosis. Notably, the promotion of Autophagy flux and an augmented resistance to OS are instrumental in curbing Pyroptosis in these flaps. Activation of TFE3 by FFA promoted Autophagy and diminished oxidative damage. The therapeutic effects of FFA were negated when TFE3 levels were decreased using adeno-associated virus (AAV)-TFE3shRNA. Additionally, FFA modified TFE3 activity through the AMPK-TRPML1-Calcineurin pathway.

Conclusions: FFA promotes ischemic FLAP survival via induction of Autophagy and suppression of OS by activation of the AMPK-TRPML1-Calcineurin-TFE3 signaling pathway. These findings could have therapeutic implications.

Keywords

Autophagy; FFA; Ischemic flaps; Oxidative stress; TFE3.

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