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

• Published in: Toxicology and applied pharmacology 2024-09, Vol.490, p.117038, Article 117038
• Main Authors: Abdulaal, Wesam H., Omar, Ulfat M., Zeyadi, Mustafa, El-Agamy, Dina S., Alhakamy, Nabil A., Ibrahim, Sabrin R.M., Almalki, Naif A.R., Asfour, Hani Z., Al-Rabia, Mohammed W., Mohamed, Gamal A., Elshal, Mahmoud
• Format: Article
• Language: English
• Subjects: 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; Cholestatic liver injury; Cyclin D1 - metabolism; FXR; Health and wellbeing; Industrial development; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice, Inbred BALB C; NF-kappa B p50 Subunit - metabolism; Oxidation-Reduction; Pirfenidone; Pyridones - therapeutic use; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction - drug effects; Tumor Necrosis Factor-alpha - metabolism; Wnt/GSK-3β/β-catenin/cyclin D1
• ISSN: 0041-008X; 1096-0333; 1096-0333
• DOI: 10.1016/j.taap.2024.117038

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. [Display omitted] •Pirfenidone protects against ANIT-induced cholestatic liver injury in mice.•Pirfenidone upregulates FXR and the bile acid efflux channels BSEP and MRP2.•Pirfenidone inhibits NF-κB/TNF-α signaling in ANIT-stimulated mice.•Pirfenidone modulates Wnt/GSK-3β/β-catenin/cyclin D1 signaling in ANIT-stimulated mice.