PT - JOURNAL ARTICLE AU - Melanie Tran AU - Jianguo Wu AU - Li Wang AU - Dong-Ju Shin TI - A potential role for SerpinA3N in acetaminophen-induced hepatotoxicity AID - 10.1124/molpharm.120.000117 DP - 2021 Jan 01 TA - Molecular Pharmacology PG - MOLPHARM-AR-2020-000117 4099 - http://molpharm.aspetjournals.org/content/early/2021/01/12/molpharm.120.000117.short 4100 - http://molpharm.aspetjournals.org/content/early/2021/01/12/molpharm.120.000117.full AB - Acetaminophen (APAP) is a commonly used pain and fever reliver but is also the most frequent cause of drug induced liver injury. The mechanism pertaining acetaminophen toxicity has been well documented, while mechanisms of hepatotoxicity are not well established. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N), a serine protease inhibitor, is synthesized in the liver but the role of SerpinA3N in relation to APAP-induced liver injury is not known. Wildtype (WT) and hepatocyte SerpinA3N knockout (HKO) mice were injected intraperitoneally with a single dose of phosphate buffered solution (PBS) or APAP (400 mg/kg) for 12 hours, and markers of liver injury, cell death, inflammation and autophagy were assessed. SerpinA3N expression was highly induced in mice with APAP overdose. SerpinA3N HKO mice had diminished liver injury and necrosis as shown by reduced alanine aminotransferase (ALT) and interleukin (IL)-6 levels, accompanied by suppressed inflammatory cytokines and reduced neutrophil infiltration. The reduced oxidative stress was associated with enhanced antioxidant enzyme capabilities. Taken together, hepatocyte SerpinA3N deficiency reduced APAP-induced liver injury by ameliorating inflammation and modulating the 5' AMP-activated protein kinase-unc-51 like autophagy activating kinase 1 (AMPK-ULK1) signaling pathway. Our study provides novel insights into a potential role for SerpinA3N in APAP-induced liver injury. Significance Statement Our studies indicate that SerpinA3N may have a pathophysiological role in modulating APAP-induced liver injury. More specifically, mice with hepatic deletion of SerpinA3N suppressed inflammation and liver injury to reduce APAP induced hepatotoxicity. Controlling the inflammatory response offers possible approaches for novel therapeutics, therefore understanding the pathophysiological role of SerpinA3N in inducing liver toxicity may add to the development of more efficacious treatments.