Cross-talk between the RAS-ERK and mTOR signalings-associated autophagy contributes to tripterygium glycosides tablet-induced liver injury

Xiaoyue Wang; Yi Zhang; Zihe Ding; Lijing Du; Yanqiong Zhang; Shikai Yan; Na Lin

doi:10.1016/j.biopha.2023.114325

Cross-talk between the RAS-ERK and mTOR signalings-associated autophagy contributes to tripterygium glycosides tablet-induced liver injury

Biomed Pharmacother. 2023 Apr:160:114325. doi: 10.1016/j.biopha.2023.114325. Epub 2023 Feb 2.

Authors

Xiaoyue Wang¹, Yi Zhang¹, Zihe Ding¹, Lijing Du², Yanqiong Zhang³, Shikai Yan⁴, Na Lin⁵

Affiliations

¹ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
² School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
³ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: yqzhang@icmm.ac.cn.
⁴ School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: shkyan@sjtu.edu.cn.
⁵ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: nlin@icmm.ac.cn.

PMID: 36738501
DOI: 10.1016/j.biopha.2023.114325

Abstract

Background and aims: Drug-induced liver injury (DILI) remains a critical issue and a hindrance to clinical application of Tripterygium Glycosides Tablet (TGT) despite its favorable therapeutic efficacy in rheumatoid arthritis. Herein, we aimed to elucidate the molecular mechanisms underlying TGT-induced hepatotoxicity.

Methods: Chemical profiling of TGT was identified by UPLC-Q/TOF-MS/MS and its putative targets were predicted based on chemical structure similarity calculation. Following "DILI-related gene-TGT putative target" interaction network construction, a list of key network targets was screened according to nodes' topological importance and functional relevance. Both in vivo and in vitro experiments were performed to determine drug hepatotoxicity and the underlying mechanisms.

Result: A total of 49 chemical components and 914 putative targets of TGTs were identified. Network calculation and functional modularization screened RAS-ERK and mTOR signalings-associated autophagy to be one of the candidate targets of TGT-induced hepatotoxicity. Experimentally, TGT significantly activated RAS-ERK axis, elevated the number of autophagosomes and the expression of LC3II protein, but reduced the expression of p62 protein and suppressed mTOR phosphorylation in the liver tissues of TGT-induced acute liver injury mice and chronic liver injury mice in vivo and AML12 cells in vitro. Moreover, TGT and mL-098 (an activator of RAS) co-treatment reduced AML12 cell viability via regulating autophagy and TGT-induced liver injury-related indicators more dramatically than TGT treatment alone, whereas Salirasib (an inhibitor of RAS) had an opposite effect.

Conclusion: RAS-ERK-mTOR cross-talk may play a crucial role in TGT-induced hepatocyte autophagy, offering a promising target for developing novel therapeutics to combat TGT-induced hepatotoxicity.

Keywords: Autophagy; Drug-induced liver injury; RAS-ERK-mTOR cross-talk; Tripterygium glycosides tablet; UPLC-Q/TOF-MS/MS.

MeSH terms

Animals
Autophagy
Chemical and Drug Induced Liver Injury* / drug therapy
Chemical and Drug Induced Liver Injury, Chronic* / drug therapy
Drugs, Chinese Herbal* / therapeutic use
Glycosides / pharmacology
Glycosides / therapeutic use
Liver
Mice
TOR Serine-Threonine Kinases
Tablets / chemistry
Tandem Mass Spectrometry
Tripterygium / chemistry

Substances

Drugs, Chinese Herbal
Glycosides
Tablets
TOR Serine-Threonine Kinases