High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice.
Acta Pharm Sin B
; 14(1): 190-206, 2024 Jan.
Article
in En
| MEDLINE
| ID: mdl-38261809
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Language:
En
Journal:
Acta Pharm Sin B
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Países Bajos