Loganin ameliorates acetaminophen-induced acute liver injury via targeting TOP1MT-mediated hepatocyte apoptosis and ferroptosis

Abstract Acetaminophen (APAP) overdose can cause severe liver injury, and new drugs are urgent needed for effective treatment. Small molecules in Chinese medicine have long been a treasured reservoir for drugs screening. Here, we reported that loganin (LOG), an active ingredient in Corni Fructus, exerts hepatoprotective effects as indicated by potently alleviated liver damages in APAP-induced liver injury (AILI) murine model. LOG reversed the decreased SOD, GSH and CAT levels, and reduced lipid peroxidation, ROS production, and iron overload and hence reduced apoptosis/ferroptosis of hepatocytes of AILI models, as apoptosis/ferroptosis inducers abolished, whereas their inhibitors enhanced the effect of LOG. Through the activity-based proteome profiling (ABPP) clickable alkyne-tagged LOG probe, mitochondrial topoisomerase I (TOP1MT) was captured as a direct target of LOG, which was further validated by CETSA and ITC assays. Deficiency of TOP1MT significantly compromised the effects of LOG on H2O2-induced oxidative stress cell model via regulating downstream apoptosis/ferroptosis regulators Bax, Bcl-2, NRF2, GSH, SLC7A11, and GPX4. Consistently, LOG effect was greatly eliminated in AILI mice once the endogenous hepatic TOP1MT was knocked-down by AAV-TOP1MT shRNA. Thus, TOP1MT might be a potential target for AILI treatment and LOG represents one of the most promising candidate drugs or lead compounds.