Samotolisib Attenuates Acute Liver Injury Through Inhibiting Caspase-11-Mediated Pyroptosis Via Regulating E3 Ubiquitin Ligase Nedd4.
Samotolisib Attenuates Acute Liver Injury Through Inhibiting Caspase-11-Mediated Pyroptosis Via Regulating E3 Ubiquitin Ligase Nedd4.
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Samotolisib 通过调节 E3 泛素连接酶 Nedd4 抑制 Caspase-11 介导的细胞焦亡，从而减轻急性肝损伤
DOI：
10.3389/fphar.2021.726198
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发表时间：
2021
影响因子：
5.6
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Zhao YY;Wu DM;He M;Zhang F;Zhang T;Liu T;Li J;Li L;Xu Y
急性肝损伤（ALI）与脓毒症患者的生存率低有关。在脓毒症期间，肝脏是细菌内毒素诱导的炎症的主要部位。脂多糖（LPS）促进半胱天冬酶-4/5/11活化，导致焦亡，一种主要的脓毒症驱动因素。本研究的目的是确定新的药物，可以控制肝细胞caspase-4/5/11激活脓毒症。我们在RAW 264.7细胞中进行了LPS诱导的caspase-11活化和焦亡，并建立了LPS诱导的ALI小鼠模型。我们通过筛选具有已知靶点的441种pyroptosis化合物的文库，鉴定了samotolisib（ST），一种新型的双重磷酸肌醇3-激酶（PI 3 K）和雷帕霉素（mTOR）靶点抑制剂，其剂量依赖性地抑制caspase-11活化和gasdermin D的N-末端片段（GSDMD-NT）生成，减少RAW 264.7细胞的pyroptosis。在小鼠中，ST预处理改善了存活率，减弱了LPS诱导的血清丙氨酸转氨酶和天冬氨酸转氨酶活性，并抑制了严重的肝脏炎症和损伤。重要的是，ST处理激活了Nedd 4，Nedd 4直接与caspase-11相互作用并介导caspase-11的泛素化和降解。这在很大程度上被胰岛素样生长因子1废除。ST通过调节PI 3 K/AKT/mTOR/Nedd 4信号通路，抑制caspase-11/GSDMD-NT信号通路，减轻LPS诱导的肝毒性。因此，ST可能在预防脓毒症患者的肝损伤中发挥关键作用。
Acute liver injury (ALI) is associated with poor survival in patients with sepsis. During sepsis, the liver is the main site of bacterial endotoxin-induced inflammation. Lipopolysaccharide (LPS) promotes caspase-4/5/11 activation, leading to pyroptosis, a major sepsis driver. This study aimed to identify novel drugs that can control hepatocyte caspase-4/5/11 activation during sepsis. We performed LPS-induced caspase-11 activation and pyroptosis in RAW 264.7 cells and established an LPS-induced ALI mouse model. We identified samotolisib (ST), a novel dual phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, by screening a library of 441 pyroptosis compounds with known targets, which dose-dependently inhibited caspase-11 activation and N-terminal fragment of gasdermin D (GSDMD-NT) generation, reducing RAW 264.7 cell pyroptosis. In mice, ST preconditioning improved survival, attenuated LPS-induced serum alanine aminotransferase and aspartate aminotransferase activity, and inhibited severe liver inflammation and damage. Importantly, ST treatment activated Nedd4, which directly interacts with and mediates caspase-11 ubiquitination and degradation. This was largely abrogated by insulin-like growth factor 1. ST ameliorated LPS-induced hepatotoxicity by inhibiting caspase-11/GSDMD-NT pyroptosis signaling via regulating PI3K/AKT/mTOR/Nedd4 signaling. Hence, ST may play a key role in the prevention of liver injury in patients with sepsis.
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影响因子：
8.7
作者：
Man SM;Karki R;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
32.4
作者：
Duong, Bao H.;Onizawa, Michio;Oses-Prieto, Juan A.;Advincula, Rommel;Burlingame, Alma;Malynn, Barbara A.;Ma, Averil
通讯作者：
Ma, Averil
影响因子：
4.8
作者：
Campbell, Grant R.;Bruckman, Rachel S.;Spector, Stephen A.
通讯作者：
Spector, Stephen A.
影响因子：
7.3
作者：
Cao XR;Lill NL;Boase N;Shi PP;Croucher DR;Shan H;Qu J;Sweezer EM;Place T;Kirby PA;Daly RJ;Kumar S;Yang B
通讯作者：
Yang B
DOI：
10.1126/science.1240988
发表时间：
2013-09-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hagar JA;Powell DA;Aachoui Y;Ernst RK;Miao EA
通讯作者：
Miao EA