Pirfenidone ameliorates ANIT-induced cholestatic liver injury via modulation of FXR, NF-кB/TNF-α, and Wnt/GSK-3β/β-catenin signaling pathways

Toxicol Appl Pharmacol. 2024 Sep:490:117038. doi: 10.1016/j.taap.2024.117038. Epub 2024 Jul 15.

Abstract

Cholestasis is a hepatobiliary disorder characterized by the excessive accumulation of toxic bile acids in hepatocytes, leading to cholestatic liver injury (CLI) through multiple pathogenic inflammatory pathways. Currently, there are limited therapeutic options for the management of cholestasis and associated CLI; therefore, new options are urgently needed. Pirfenidone (PF), an oral bioavailable pyridone analog, is used for the treatment of idiopathic pulmonary fibrosis. PF has recently demonstrated diverse potential therapeutic activities against different pathologies. Accordingly, the present study adopted the α-naphthyl isothiocyanate (ANIT)-induced CLI model in mice to explore the potential protective impact of PF and investigate the underlying mechanisms of action. PF intervention markedly reduced the serum levels of ALT, AST, LDH, total bilirubin, and total bile acids, which was accompanied by a remarkable amelioration of histopathological lesions induced by ANIT. PF also protected the mice against ANIT-induced redox imbalance in the liver, represented by reduced MDA levels and elevated GSH and SOD activities. Mechanistically, PF inhibited ANIT-induced downregulated expressions of the farnesoid X receptor (FXR), as well as the bile salt export pump (BSEP) and the multidrug resistance-associated protein 2 (MRP2) bile acid efflux channels. PF further repressed ANIT-induced NF-κB activation and TNF-α and IL-6 production. These beneficial effects were associated with its ability to dose-dependently inhibit Wnt/GSK-3β/β-catenin/cyclin D1 signaling. Collectively, PF protects against ANIT-induced CLI in mice, demonstrating powerful antioxidant and anti-inflammatory activities as well as an ability to oppose BA homeostasis disorder. These protective effects are primarily mediated by modulating the interplay between FXR, NF-κB/TNF-α/IL-6, and Wnt/β-catenin signaling pathways.

Keywords: Cholestatic liver injury; FXR; Health and wellbeing; Industrial development; Pirfenidone; Wnt/GSK-3β/β-catenin/cyclin D1.

MeSH terms

  • 1-Naphthylisothiocyanate / toxicity
  • Animals
  • Chemical and Drug Induced Liver Injury* / drug therapy
  • Chemical and Drug Induced Liver Injury* / metabolism
  • Chemical and Drug Induced Liver Injury* / pathology
  • Cholestasis* / chemically induced
  • Cholestasis* / drug therapy
  • Cholestasis* / metabolism
  • Cholestasis* / pathology
  • Cyclin D1 / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice, Inbred BALB C
  • NF-kappa B p50 Subunit / metabolism
  • Oxidation-Reduction
  • Pyridones* / therapeutic use
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction* / drug effects
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • pirfenidone
  • Pyridones
  • farnesoid X-activated receptor
  • Receptors, Cytoplasmic and Nuclear
  • Nfkb1 protein, mouse
  • NF-kappa B p50 Subunit
  • Tumor Necrosis Factor-alpha
  • Ccnd1 protein, mouse
  • Cyclin D1
  • 1-Naphthylisothiocyanate