Piezo1 alleviates acetaminophen-induced acute liver injury by activating Nrf2 and reducing mitochondrial reactive oxygen species

Biochem Biophys Res Commun. 2023 Apr 16:652:88-94. doi: 10.1016/j.bbrc.2023.02.043. Epub 2023 Feb 18.

Abstract

Acetaminophen (APAP) overdose is the most common cause for acute liver failure (ALF) in the developed countries, with limited treatment options. Piezo1 is a mechanosensitive cation channel. We found that APAP caused upregulation of Piezo1 in both an APAP-induced acute liver injury (ALI) animal model and a mouse hepatocyte cell line AML12. Activation of Piezo1 by its activator Yoda1 reduced APAP-induced hepatotoxicity and ROS level. Mechanistically, activation of Piezo1 led to accumulation of the antioxidant regulator Nrf2 and upregulation of its target genes Nqo1 and Gsta1, while knockdown of Piezo1 downregulated this pathway. Finally, injection of Yoda1 decreased serum AST and ALT levels, reduced cell death and rescued liver injury in the APAP-induced ALI mouse model. Our findings suggested a previously undiscovered protective role of Piezo1 in APAP-induced ALI, which might shed light on a new therapeutic target for this disease.

Keywords: Acetaminophen; Acute liver injury; Nrf2; Piezo1; Reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen*
  • Animals
  • Chemical and Drug Induced Liver Injury* / metabolism
  • Hepatocytes / metabolism
  • Ion Channels / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Acetaminophen
  • NF-E2-Related Factor 2
  • Piezo1 protein, mouse
  • Ion Channels