PDF(Pubmed)
Abstract：
Our work aimed to investigate the interactive roles of transforming growth factor β1 (TGF-β1), ubiquitin-specific-processing protease 7 (USP7), and Yes-associated protein (YAP) in ferroptosis during sepsis-secondary acute lung injury (ALI). Our study demonstrated that ferroptosis was aggravated by TGF-β1 in both cellular and animal models of acute lung injury. Additionally, YAP upregulated glutathione peroxidase 4 (GPX4) and SLC7A11 by regulating the binding of TEAD4 to GPX4/SLC7A11 promoters. Furthermore, large tumor suppressor kinase 1 (LATS1) knockdown resulted in YAP expression stimulation, while USP7 downregulated YAP via deubiquitinating and stabilizing LATS1/2. YAP overexpression or USP7/LATS1 silencing reduced ferroptosis process, which regulated YAP through a feedback loop. However, TGF-β1 annulled the repression of ferroptosis by YAP overexpression or LATS1/USP7 knockdown. By elucidating the molecular interactions between TGF-β1, USP7, LATS1/2, and YAP, we identified a new regulatory axis of ferroptosis in sepsis-secondary ALI. Our study sheds light on the pathophysiology of ferroptosis and proposes a potential therapeutic approach for sepsis-induced ALI.
摘要：
我们的工作旨在探讨转化生长因子β1（TGF-β1）的相互作用作用，泛素特异性加工蛋白酶7（USP7），和Yes相关蛋白（YAP）在脓毒症继发性急性肺损伤（ALI）期间铁凋亡中的作用。我们的研究表明，在急性肺损伤的细胞和动物模型中，TGF-β1加重了铁死亡。此外,YAP通过调节TEAD4与GPX4/SLC7A11启动子的结合来上调谷胱甘肽过氧化物酶4(GPX4)和SLC7A11。此外，大肿瘤抑制激酶1（LATS1）敲低导致YAP表达刺激，而USP7通过去泛素化和稳定LATS1/2下调YAP。YAP过表达或USP7/LATS1沉默减少铁凋亡过程，通过反馈回路调节YAP。然而,TGF-β1通过YAP过表达或LATS1/USP7敲低消除铁死亡的抑制。通过阐明TGF-β1，USP7，LATS1/2和YAP之间的分子相互作用，我们在脓毒症继发性ALI中发现了一个新的铁凋亡调节轴.我们的研究揭示了铁死亡的病理生理学，并提出了脓毒症诱导的ALI的潜在治疗方法。
