首页|High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice

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

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Macroautophagy(referred to as autophagy hereafter)is a major intracellular lysosomal degra-dation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles.Pre-vious 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.Mecha-nistically,overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogen-esis 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.

AutophagyDILIDrug screeningHepatotoxicityLysosomeMitochondriaMitophagyNRF2

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

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Department of Pharmacology,Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS 66160,USA

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

Institute of Precision Medicine,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510515,China

Department of Oncology,the First Affiliated Hospital of Anhui Medical University,Anhui Medical University,Hefei 230032,China

National Center for Advancing Translational Sciences,National Institutes of Health,Bethesda,MD 20892,USA

Telethon Institute of Genetics and Medicine,TIGEM,Pozzuoli,Naples 80131,Italy

Medical Genetics,Department of Translational Medicine,Federico Ⅱ University,Naples 80131,Italy

Department of Molecular and Human Genetics,Baylor College of Medicine,Houston,TX 77030,USA

Department of Internal Medicine,Division of Gastroenterology,Hepatology & Motility,University of Kansas Medical Center,Kansas City,KS 66160,USA

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National Institute of Health(NIH,USA)fundsNational Institute of Health(NIH,USA)fundsNational Institute of Health(NIH,USA)fundsIntramural Research Program of the National Center for Advancing Translational Sciences,NIH(USA)

R01 DK102142R01 AG072895R37 AA020518WXD

2024

10.1016/j.apsb.2023.10.017

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(1)
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