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.
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.
Biomed Pharmacother. 2024 Aug;177:116918. doi: 10.1016/j.biopha.2024.116918. Epub 2024 Jun 15.
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.
随意皮瓣是缺损后皮肤重建的重要方法；然而，由于营养供应不足，皮瓣的远端不易存活。恩拉霉素是一种成熟的铁死亡诱导剂，但我们的研究发现，低浓度的恩拉霉素（2μM）可能会减少人脐静脉内皮细胞（HUVECs）中因营养缺乏引起的细胞死亡。RNA-seq 分析表明，其作用与自噬调节有关。后续研究表明，在 HUVECs 中使用自噬抑制剂或敲低 TFEB 均可降低恩拉霉素对 HUVECs 的抗凋亡作用。机制研究表明，恩拉霉素可以抑制 HUVECs 中的 mTORC1 并促进 TFEB 活性，表明恩拉霉素在营养缺乏条件下对 HUVECs 存活的影响受 mTORC1/TFEB 调节。随后，我们在体内评估了恩拉霉素对小鼠随意皮瓣存活的影响。术后第 7 天，我们观察到恩拉霉素处理后皮瓣存活面积、血液灌注和微血管密度显著增加；此外，恩拉霉素处理显示缺血区域的自噬增强。总之，我们的研究表明，低浓度的恩拉霉素可能抑制内皮细胞在营养缺乏条件下的细胞死亡，其作用可能与 mTORC1-TFEB 介导的自噬调节有关，恩拉霉素治疗可能是随意皮瓣的一种潜在治疗方法。
