P19-08 Amelioration of acetaminophen-induced oxidative stress and inflammation by RNAi targeting Cyp2e1in vivo

Drug-induced liver injury (DILI) is a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). CYP2E1 has been confirmed as a vital enzyme responding to production of APAP toxic metabolites and development of APAP-induced liver injury (AILI). In this study, we investigated the therapeutic effects and mechanisms of lipid nanoparticles (LNP) delivering small interfering RNA (siRNA) targeting Cyp2e1 (si- Cyp2e1 LNPs) on AILI in mice. C57BL/6J male mice were injected with 300 mg/kg APAP to establish DILI model and were given si- Cyp2e1 LNPs via the tail vein for treatment. The results demonstrated that serum levels of ALT and AST were decreased in APAP mice treated with si- Cyp2e1 LNPs immediately. Moreover, si- Cyp2e1 LNPs notably alleviated hepatic tissue inflammation and edema. Meanwhile, si- Cyp2e1 LNPs significantly alleviates oxidative stress in mice induced by APAP. Through RNA sequencing analysis, we found that si- Cyp2e1 LNPs exerted regulatory effects on pathway and genes related to PPAR. In addition, qPCR and western blot results indicated that si- Cyp2e1 LNPs downregulated Cd36 , Pparα , Pparα -target genes ( Cyp4a10 , Cyp4a14 and Fabp1 ) and inflammation-related genes ( Il-6,Il-1β and Tnf-α ) at the mRNA level and CYP4A, CD36 and FABP1 at the protein level, implying that si- Cyp2e1 LNPs exerted its effects by regulating genes related to PPAR signaling pathway. In conclusion, this study demonstrated that si- Cyp2e1 LNPs may amelioration APAP-induced oxidative stress and inflammation in mice by regulating PPAR signaling pathway.