Abstract
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.
Highlights
Acute liver injury (ALI) occurs at any stage of sepsis and is an independent risk factor for sepsis-induced death (Sun et al, 2020)
The primary antibodies used in this study were as follows: antiNLRP3, anti-IL-18, anti-IL-1β, anti-ASC, anti-caspase-1, and antiGSDMD-N purchased from Abcam (Cambridge, United Kingdom); anti-Caspase-11 purchased from Santa Cruz Biotechnology (Dallas, United States of America); anti-ubiquitin (10201-2-AP), anti-Nedd4 (21698-1-AP), antiGAPDH (60004-1-Ig), and horseradish peroxidase (HRP)conjugated secondary antibodies (SA00001-2) purchased from Proteintech (Wuhan, China); and anti-Neutrophil purchased from Biosynthesis Biotechnology Co. (Beijing, China)
The present study revealed that ST inhibits caspase-11 activation, thereby reducing the impact of pyroptosis in hepatocytes
Summary
Acute liver injury (ALI) occurs at any stage of sepsis and is an independent risk factor for sepsis-induced death (Sun et al, 2020). Sepsis is characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer et al, 2016). It is a common cause of death in intensive care units (Bauer et al, 2020). Clinical and experimental data suggest that liver dysfunction is an early sign of sepsis, and early hepatic dysfunction in patients with sepsis is a specific and independent risk factor for poor outcomes (Kramer et al, 2007). There is no specific therapy for sepsis-induced liver injury
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