Peroxiredoxin 3 Inhibits Acetaminophen-Induced Liver Pyroptosis Through the Regulation of Mitochondrial ROS.

Yue Wang,Ruixi Li,Boyang Zou,Yan Zhao,Shili Ning,Zhecheng Wang,Junjun Zhou,Xiaofeng Tian,Jihong Yao,Deshun Liu,Musen Lin,Ruimin Sun

doi:10.3389/fimmu.2021.652782

Abstract

Pyroptosis is a newly discovered form of cell death. Peroxiredoxin 3 (PRX3) plays a crucial role in scavenging reactive oxygen species (ROS), but its hepatoprotective capacity in acetaminophen (APAP)-induced liver disease remains unclear. The aim of this study was to assess the role of PRX3 in the regulation of pyroptosis during APAP-mediated hepatotoxicity. We demonstrated that pyroptosis occurs in APAP-induced liver injury accompanied by intense oxidative stress and inflammation, and liver specific PRX3 silencing aggravated the initiation of pyroptosis and liver injury after APAP intervention. Notably, excessive mitochondrial ROS (mtROS) was observed to trigger pyroptosis by activating the NLRP3 inflammasome, which was ameliorated by Mito-TEMPO treatment, indicating that the anti-pyroptotic role of PRX3 relies on its powerful ability to regulate mtROS. Overall, PRX3 regulates NLRP3-dependent pyroptosis in APAP-induced liver injury by targeting mitochondrial oxidative stress.

Highlights

Acetaminophen (APAP) is one of the most commonly used analgesic and antipyretic drugs
These results suggest that pyroptosis is related to APAP-induced liver injury
Considering all of the above data, these results suggest that the effect of Peroxiredoxin 3 (PRX3) on nod-like receptor protein 3 (NLRP3) activation in APAPinduced liver pyroptosis is potentially mediated by mitochondrial ROS (mtROS)

Summary

Introduction

Acetaminophen (APAP) is one of the most commonly used analgesic and antipyretic drugs. The recommended dose is safe and effective, but overdose causes hepatotoxicity and acute liver failure (ALF) in a dose-dependent manner [1]. The initial step in APAP-mediated hepatotoxicity is the formation of the highly reactive intermediate metabolite n-acetyl-p-benzoquinone imine (NAPQI). Excessive formation of NAPQI consumes intracellular glutathione, binds to mitochondrial proteins, and impairs mitochondrial respiration, which subsequently gives rise to overwhelming. PRX3 Inhibits APAP-Induced Liver Pyroptosis mitochondrial oxidative stress that triggers signaling pathways through mitochondrial toxicity, eventually leading to cell death and sterile inflammation [2, 3]. Upon APAP overdose in mice, at least 50% of KCs exhibit a significant loss [8,9,10]. The molecular mechanism of liver cell death in APAP-induced hepatotoxic processes needs to be further elucidated

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