2. Academic Validation
  3. Erastin promotes random-pattern skin flaps survival by inducing mTORC1-TFEB mediated autophagy

Erastin promotes random-pattern skin flaps survival by inducing mTORC1-TFEB mediated autophagy

  • Biomed Pharmacother. 2024 Jun 14:177:116918. doi: 10.1016/j.biopha.2024.116918.
Ximiao Chen 1,  Xuwei Zhu 1,  Yu Chen 1,  Zihang Ruan 1,  Yekai Zhang 1,  Hongqiang Wu 2,  Xiaolei Zhang 3,  Weiyang Gao 4
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopedics, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
  • 2 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopedics, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China. Electronic address: WuHongqiang1993@wmu.edu.cn.
  • 3 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopedics, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Chinese Orthopaedic Regenerative Medicine Society, Hangzhou, Zhejiang Province, China. Electronic address: zhangxiaolei@wmu.edu.cn.
  • 4 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopedics, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China. Electronic address: gaoweiyang@wmu.edu.cn.
PMID: 38878639 DOI: 10.1016/j.biopha.2024.116918
Abstract

Random-pattern skin flaps are important method for skin reconstruction after defect; however, the distal end of flaps is not easily viable due to inadequate nutrient supply. Erastin is a well-established Ferroptosis inducer, but our study found that low-dose of erastin (2 μM) may reduce nutrient deficiency induced cell death in human umbilical vein endothelial cells (HUVECs). RNA-seq analysis suggested that its role was related to Autophagy regulation. Follow-up studies have shown that the use of Autophagy inhibitors or the knockdown of TFEB in HUVECs can both reduce the anti-apoptotic effect of erastin in HUVECs. Mechanism study demonstrated that erastin can suppress mTORC1 and promote TFEB activity in HUVECs, suggesting that the effect of erastin on the survival of HUVECs under nutrient deprivation conditions is regulated by mTORC1/TFEB. Subsequently, we evaluated the effect of erastin on the survival of random-pattern skin flaps in mice in vivo. On the postoperative day 7, we observed a significant increase in FLAP survival area, blood perfusion, and microvascular density after erastin treatment; also, erastin treatment showed enhanced Autophagy within the ischemic region. In summary, our study demonstrates that low-dose of erastin may suppress cell death in endothelial cells under nutrient deficiency condition, and its effects may relate to the mTORC1-TFEB medicated Autophagy regulation, erastin treatment may be a potential therapy for random-pattern skin flaps.

Keywords

Autophagy; Erastin; Nutrient deficiency; Random-pattern skin flaps; TFEB.

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