Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Princess Dr. Najla Bint Saud Al-Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah, Saudi Arabia.
Toxicol Appl Pharmacol. 2024 Sep;490:117038. doi: 10.1016/j.taap.2024.117038. Epub 2024 Jul 15.
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.
胆汁淤积症是一种肝胆疾病，其特征是肝细胞内有毒胆汁酸的过度积累，通过多种致病炎症途径导致胆汁淤积性肝损伤 (CLI)。目前，针对胆汁淤积症及其相关 CLI 的治疗选择有限，因此迫切需要新的治疗选择。吡非尼酮 (PF) 是一种口服生物利用的吡啶酮类似物，用于治疗特发性肺纤维化。PF 最近在多种不同疾病中表现出多种潜在的治疗活性。因此，本研究采用 α-萘基异硫氰酸酯 (ANIT) 诱导的 CLI 小鼠模型，探讨 PF 的潜在保护作用，并研究其作用机制。PF 干预显著降低了 ALT、AST、LDH、总胆红素和总胆汁酸的血清水平，同时显著改善了 ANIT 诱导的组织病理学损伤。PF 还保护了小鼠免受 ANIT 诱导的肝脏氧化还原失衡，表现为 MDA 水平降低和 GSH 和 SOD 活性升高。机制上，PF 抑制了 ANIT 诱导的法尼醇 X 受体 (FXR) 以及胆汁盐输出泵 (BSEP) 和多药耐药相关蛋白 2 (MRP2) 胆汁酸外排通道的下调表达。PF 进一步抑制了 ANIT 诱导的 NF-κB 激活以及 TNF-α 和 IL-6 的产生。这些有益作用与它能够剂量依赖性地抑制 Wnt/GSK-3β/β-catenin/cyclin D1 信号通路有关。综上所述，PF 可预防 ANIT 诱导的小鼠 CLI，表现出强大的抗氧化和抗炎活性以及纠正 BA 稳态紊乱的能力。这些保护作用主要是通过调节 FXR、NF-κB/TNF-α/IL-6 和 Wnt/β-catenin 信号通路之间的相互作用来介导的。
