Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway

Lei Gu; Xin He; Yanqiu Zhang; Shenglan Li; Jie Tang; Ruixue Ma; Xinyi Yang; Hao Huang; Yu Peng; Yanyun Xie; Zhangzhe Peng; Jie Meng; Gaoyun Hu; Lijian Tao; Xiaowei Liu; Huixiang Yang

Biomedicine & Pharmacotherapy (Aug 2023)

Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway

Lei Gu,
Xin He,
Yanqiu Zhang,
Shenglan Li,
Jie Tang,
Ruixue Ma,
Xinyi Yang,
Hao Huang,
Yu Peng,
Yanyun Xie,
Zhangzhe Peng,
Jie Meng,
Gaoyun Hu,
Lijian Tao,
Xiaowei Liu,
Huixiang Yang

Affiliations

Lei Gu: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
Xin He: Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China
Yanqiu Zhang: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China
Shenglan Li: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China
Jie Tang: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China
Ruixue Ma: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China
Xinyi Yang: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China
Hao Huang: Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410013, China
Yu Peng: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China
Yanyun Xie: Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China
Zhangzhe Peng: Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China; Corresponding author at: Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China.
Jie Meng: Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Respirology, Third Xiangya Hospital, Central South University, Changsha 410013, China
Gaoyun Hu: Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; Faculty of Pharmaceutical Sciences, Central South University, Changsha 410013, China
Lijian Tao: Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
Xiaowei Liu: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
Huixiang Yang: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; Corresponding author at: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China.

Journal volume & issue: Vol. 164
p. 114844

Abstract

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Aims: Acute liver failure (ALF) is a life-threatening disease characterized by abrupt and extensive hepatic necrosis and apoptosis, resulting in high mortality. The approved drug, N-acetylcysteine (NAC), is only effective for acetaminophen (APAP)-associated ALF at the early stage. Thus, we investigate whether fluorofenidone (AKF-PD), a novel antifibrosis pyridone agent, protects against ALF in mice and explore its underlying mechanisms. Methods: ALF mouse models were established using APAP or lipopolysaccharide/D-galactosamine (LPS/D-Gal). Anisomycin and SP600125 were used as JNK activator and inhibitor, respectively, and NAC served as a positive control. Mouse hepatic cell line AML12 and primary mouse hepatocytes were used for in vitro studies. Results: AKF-PD pretreatment alleviated APAP-induced ALF with decreased necrosis, apoptosis, reactive oxygen species (ROS) markers, and mitochondrial permeability transition in liver. Additionally, AKF-PD alleviated mitochondrial ROS stimulated by APAP in AML12 cells. RNA-sequencing in the liver and subsequent gene set enrichment analysis showed that AKF-PD significantly impacted MAPK and IL-17 pathway. In vitro and in vivo studies demonstrated that AKF-PD inhibited APAP-induced phosphorylation of MKK4/JNK, while SP600125 only inhibited JNK phosphorylation. The protective effect of AKF-PD was abolished by anisomycin. Similarly, AKF-PD pretreatment abolished hepatotoxicity caused by LPS/D-Gal, decreased ROS levels, and diminished inflammation. Furthermore, unlike NAC, AKF-PD, inhibited the phosphorylation of MKK4 and JNK upon pretreatment, and improved survival in cases of LPS/D-Gal-induced mortality with delayed dosing. Conclusions: In summary, AKF-PD can protect against ALF caused by APAP or LPS/D-Gal, in part, via regulating MKK4/JNK pathway. AKF-PD might be a novel candidate drug for ALF.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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