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This study suggests that excessive APAP can impair TFEB and TFEB mediated lysosomal biogenesis in mouse liver. The gene manipulation of TFEB in mouse liver showed that TFEB has a protective effect on AILI.
At therapeutic doses, acetaminophen (APAP) is a safe and effective medication, but in animals and humans, excessive use can cause severe liver damage, leading to acute liver failure. In the United States and many Western countries, excessive APAP is the most common cause of acute liver failure. This mouse model is highly correlated with apap induced liver injury (AILI) in clinical practice, therefore understanding the pathophysiology of AILI in mice has a direct clinical impact on identifying new therapeutic targets and intervention strategies.
Image from： https://doi.org/10.1016/j.apsb.2023.10.017
Recently, researchers from the University of Kansas in the United States published an article titled "High throughput screening of novel TFEB antigens in protecting against acetaminophen induced liver injury in mice" in Acta Pharm Sin B. The study suggests that gene and pharmacological activation of TFEB may be a promising method for preventing AILI.
Macroautophagy is a major pathway for lysosomal degradation in cells, responsible for degrading misfolded/damaged proteins and organelles. Previous studies have shown that autophagy protects cells from acetaminophen induced damage (AILI) by selectively removing damaged mitochondria and APAP protein adducts. Lysosomes are key organelles that undergo autophagic degradation by fusing with autophagosomes during the late stage of autophagy.
In this study, researchers found that TFEB is the main transcription factor involved in lysosomal biogenesis, which is disrupted by APAP and leads to a decrease in lysosomal biogenesis in mouse liver. The genetic loss and acquisition of liver TFEB function exacerbate or protect AILI, respectively. Mechanistically, overexpression of TFEB increases the clearance of APAP protein adducts and mitochondrial biogenesis, as well as activation of SQSTM1/p62 dependent NRF2, thereby preventing AILI. The researchers also conducted unbiased high-throughput chemical screening of TFEB based on cell imaging and identified a group of TFEB agonists. Among these agonists, salinomycin, an anti coccidioid and antibacterial drug, activates TFEB and protects mice from AILI.
Excessive exposure of APAP to salinomycin
The protective effect of mouse liver injury
images from :https://doi.org/10.1016/j.apsb.2023.10.017
In summary, this study suggests that excessive APAP can impair TFEB and TFEB mediated lysosomal biogenesis in mouse liver. The gene manipulation of TFEB in mouse liver showed that TFEB has a protective effect on AILI. More importantly, the pharmacological activation of TFEB by salinomycin (a TFEB agonist discovered from high-throughput screening) can protect mice from the effects of AILI. These findings support a potential beneficial approach to prevent AILI by targeting liver TFEB.
Reference
Xiaojuan Chao et al. High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice. Acta Pharm Sin B. 2024 Jan;14(1):190-206. doi: 10.1016/j.apsb.2023.10.017.
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