PMID- 38261809 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240125 IS - 2211-3835 (Print) IS - 2211-3843 (Electronic) IS - 2211-3835 (Linking) VI - 14 IP - 1 DP - 2024 Jan TI - High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice. PG - 190-206 LID - 10.1016/j.apsb.2023.10.017 [doi] AB - 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. CI - (c) 2024 The Authors. FAU - Chao, Xiaojuan AU - Chao X AD - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. FAU - Niu, Mengwei AU - Niu M AD - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. FAU - Wang, Shaogui AU - Wang S AD - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. FAU - Ma, Xiaowen AU - Ma X AD - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. FAU - Yang, Xiao AU - Yang X AD - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. AD - 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. FAU - Sun, Hua AU - Sun H AD - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. AD - Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei 230032, China. FAU - Hu, Xujia AU - Hu X AD - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. FAU - Wang, Hua AU - Wang H AD - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. AD - Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei 230032, China. FAU - Zhang, Li AU - Zhang L AD - National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA. FAU - Huang, Ruili AU - Huang R AD - National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA. FAU - Xia, Menghang AU - Xia M AD - National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA. FAU - Ballabio, Andrea AU - Ballabio A AD - Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples 80131, Italy. AD - Medical Genetics, Department of Translational Medicine, Federico II University, Naples 80131, Italy. AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Jaeschke, Hartmut AU - Jaeschke H AD - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. FAU - Ni, Hong-Min AU - Ni HM AD - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. FAU - Ding, Wen-Xing AU - Ding WX AD - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. AD - Department of Internal Medicine, Division of Gastroenterology, Hepatology & Motility, University of Kansas Medical Center, Kansas City, KS 66160, USA. LA - eng PT - Journal Article DEP - 20231029 PL - Netherlands TA - Acta Pharm Sin B JT - Acta pharmaceutica Sinica. B JID - 101600560 PMC - PMC10793101 OTO - NOTNLM OT - Autophagy OT - DILI OT - Drug screening OT - Hepatotoxicity OT - Lysosome OT - Mitochondria OT - Mitophagy OT - NRF2 COIS- A. Ballabio is co-founder of CASMA Therapeutics and Advisory board member of Next Generation Diagnostics and Avilar Therapeutics. EDAT- 2024/01/23 18:42 MHDA- 2024/01/23 18:43 PMCR- 2023/10/29 CRDT- 2024/01/23 15:53 PHST- 2023/08/25 00:00 [received] PHST- 2023/09/12 00:00 [revised] PHST- 2023/09/15 00:00 [accepted] PHST- 2024/01/23 18:43 [medline] PHST- 2024/01/23 18:42 [pubmed] PHST- 2024/01/23 15:53 [entrez] PHST- 2023/10/29 00:00 [pmc-release] AID - S2211-3835(23)00411-2 [pii] AID - 10.1016/j.apsb.2023.10.017 [doi] PST - ppublish SO - Acta Pharm Sin B. 2024 Jan;14(1):190-206. doi: 10.1016/j.apsb.2023.10.017. Epub 2023 Oct 29.