miR-375 protects against APAP-induced acute liver failure by orchestrating pharmacogene expression

Acetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF), primarily through the excessive production of N-acetyl-p-benzoquinone imine (NAPQI). N-acetylcysteine (NAC) is the FDA-approved treatment for APAP overdose, but there is a growing interest in microRNAs (miRNAs) as potential therapeutic agents. This study aims to evaluate the protective role of miR-375 in APAP-induced ALF and elucidate its underlying mechanisms. We delivered miR-375 ectopically via a liver-tropic adeno-associated virus serotype 8 (AAV8) to examine its protection in a murine model of APAP overdose-induced ALF. We found that ectopic miR-375 protects against APAP-ALF by modulating the expression of pharmacogenes and enhancing glutathione synthesis.