High-throughput screening of novel TFEB agonists in protecting against acetaminopheninduced liver injury in mice  

作　　者：Xiaojuan Chao Mengwei Niu Shaogui Wang Xiaowen Ma Xiao Yang Hua Sun Xujia Hu Hua Wang Li Zhang Ruili Huang Menghang Xia Andrea Ballabio Hartmut Jaeschke Hong-Min Ni Wen-Xing Ding 

机构地区：[1]Department of Pharmacology,Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS 66160,USA [2]NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China [3]Department of Oncology,the First Affiliated Hospital of Anhui Medical University,Anhui Medical University,Hefei 230032,China [4]National Center for Advancing Translational Sciences,National Institutes of Health,Bethesda,MD 20892,USA [5]Telethon Institute of Genetics and Medicine,TIGEM,Pozzuoli,Naples 80131,Italy [6]Medical Genetics,Department of Translational Medicine,Federico II University,Naples 80131,Italy [7]Department of Molecular and Human Genetics,Baylor College of Medicine,Houston,TX 77030,USA [8]Department of Internal Medicine,Division of Gastroenterology,Hepatology&Motility,University of Kansas Medical Center,Kansas City,KS 66160,USA

出　　处：《Acta Pharmaceutica Sinica B》2024年第1期190-206,共17页药学学报（英文版）

基　　金：We would like to thank Dr.Thomas Ru¨licke at Department of Biomedical Sciences,University of Veterinary Medicine Vienna,Vienna,Austria and Dr.Kurt Zatloukal at The Institute of Pathology,Medical University of Graz,A-8036 Graz,Austria for providing us whole body Sqstm1/p62 knockout mice for the hepatocyte isolation experiment.We also thank Larysa Stroganova at University of Kansas Medical Center for her excellent assistance for the EM studies.This study was supported in part by the National Institute of Health(NIH,USA)funds R01 DK102142,R01 AG072895,R37 AA020518(WXD)and in part by the Intramural Research Program of the National Center for Advancing Translational Sciences,NIH(USA).

摘　　要：Macroautophagy(referred to as autophagy hereafter)is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles.Previous studies showed that autophagy protects against acetaminophen(APAP)-induced injury(AILI)via selective removal of damaged mitochondria and APAP protein adducts.The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes.In the present study,we showed that transcription factor EB(TFEB),a master transcription factor for lysosomal biogenesis,was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers.Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI,respectively.Mechanistically,overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2(NRF2)activation to protect against AILI.We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists.Among these agonists,salinomycin,an anticoccidial and antibacterial agent,activated TFEB and protected against AILI in mice.In conclusion,genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.

关 键 词：Autophagy DILI Drug screening HEPATOTOXICITY LYSOSOME MITOCHONDRIA MITOPHAGY NRF2 

分 类 号：R96[医药卫生—药理学]