Abstract：
The precise mechanism of ferroptosis as a regulatory cell death in intestinal ischemia injury induced by vascular intestinal obstruction (Vio) remains to be elucidated. Here, we evaluated iron levels, glutathione peroxidase 4 (GPX4) and Acyl-CoA synthetase long-chain family member 4 (ACSL4) changes after intestinal ischemia injury to validate ferroptosis. As an enzyme for Fe3+ reduction to Fe2+, Ferric Chelate Reductase 1 (FRRS1) is involved in the electron transport chain and the tricarboxylic acid (TCA) cycle in mitochondria. However, whether it is involved in ferroptosis and its role in intestinal ischemia injury need to be clarified. In the present study, FRRS1 was overexpressed in vivo and in vitro. The results showed that overexpression of FRRS1 prevented ischemia-induced iron levels, reactive oxygen species (ROS) production, lipid peroxidation, inflammatory responses, and cell death. Meanwhile, FRRS1 overexpression promoted GPX4 expression and suppressed ACSL4 levels. Further studies revealed that FRRS1 overexpression inhibited the activity of large tumor suppressor 1 (LATS1) / Yes-associated protein (YAP) / transcriptional co-activator with PDZ-binding motif (TAZ), a key component of Hippo signaling. In conclusion, this study demonstrates that FRRS1 is intimately involved in the inhibition of ferroptosis and thus protection of the intestine from intestinal ischemia injury, its downstream mechanism was related to Hippo signaling. These data provide new sight for the prevention and treatment of intestinal ischemia injury.
摘要：
在血管性肠梗阻（Vio）引起的肠缺血损伤中，铁凋亡作为调节性细胞死亡的确切机制仍有待阐明。这里,我们评估了铁水平，谷胱甘肽过氧化物酶4（GPX4）和酰基辅酶A合成酶长链家族成员4（ACSL4）在肠缺血损伤后的变化以验证铁凋亡。作为Fe3+还原为Fe2+的酶，铁螯合还原酶1（FRRS1）参与线粒体中的电子传递链和三羧酸（TCA）循环。然而,是否参与铁凋亡及其在肠缺血损伤中的作用尚需明确。在本研究中,FRRS1在体内和体外过表达。结果表明，FRRS1的过表达阻止了缺血诱导的铁水平，活性氧（ROS）的产生，脂质过氧化，炎症反应，细胞死亡。同时,FRRS1过表达促进GPX4表达并抑制ACSL4水平。进一步的研究表明，FRRS1过表达抑制了具有PDZ结合基序（TAZ）的大肿瘤抑制因子1（LATS1）/Yes相关蛋白（YAP）/转录共激活因子的活性，河马信号的关键组成部分。总之,这项研究表明，FRRS1密切参与抑制铁凋亡，从而保护肠免受肠缺血损伤，其下游机制与Hippo信号有关。这些数据为肠缺血毁伤的预防和医治供给了新的景象。
