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

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

Return

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

Author: Xiaojuan CHAO ¹ ; Mengwei NIU ¹ ; Shaogui WANG ¹ ; Xiaowen MA ¹ ; Xiao YANG ¹ ; Hua SUN ¹ ; Xujia HU ¹ ; Hua WANG ¹ ; Li ZHANG ² ; Ruili HUANG ² ; Menghang XIA ² ; Andrea BALLABIO ³ ; Hartmut JAESCHKE ¹ ; Hong-Min NI ¹ ; Wen-Xing DING ¹
Author Information

1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
2. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA.
3. Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples 80131, Italy.
Publication Type:Journal Article
Keywords: Autophagy; DILI; Drug screening; Hepatotoxicity; Lysosome; Mitochondria; Mitophagy; NRF2
From: Acta Pharmaceutica Sinica B 2024;14(1):190-206
CountryChina
Language:English
Abstract: 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.