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 

作者机构：Department of PharmacologyToxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKS 66160USA NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Department of Oncologythe First Affiliated Hospital of Anhui Medical UniversityAnhui Medical UniversityHefei 230032China National Center for Advancing Translational SciencesNational Institutes of HealthBethesdaMD 20892USA Telethon Institute of Genetics and MedicineTIGEMPozzuoliNaples 80131Italy Medical GeneticsDepartment of Translational MedicineFederico II UniversityNaples 80131Italy Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTX 77030USA Department of Internal MedicineDivision of GastroenterologyHepatology&MotilityUniversity of Kansas Medical CenterKansas CityKS 66160USA 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2024年第14卷第1期

页      面：190-206页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

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) 

主　　题：Autophagy DILI Drug screening Hepatotoxicity Lysosome Mitochondria Mitophagy NRF2 

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 *** studies showed that autophagy protects against acetaminophen(APAP)-induced injury(AILI)via selective removal of damaged mitochondria and APAP protein *** lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with *** 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 *** loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI,***,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 *** also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB *** these agonists,salinomycin,an anticoccidial and antibacterial agent,activated TFEB and protected against AILI in *** conclusion,genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.