Amelioration of Acetaminophen-Induced Hepatic Oxidative Stress and Inflammation by RNAi Targeting Cyp2e1 In Vivo.

The overdose of acetaminophen (APAP) has become the leading cause of acute liver failure in the United States and some Western countries. As a principal member of the cytochrome P450 enzymes (CYPs), CYP2E1 is a vital enzyme in regard to the production of toxic APAP metabolites and in the development of APAP-induced liver injury (AILI). In this study, we investigated the therapeutic effects and mechanisms of lipid nanoparticle (LNP)-based delivery of small interfering RNA targeting Cyp2e1 (si-Cyp2e1 LNPs) on AILI in mice. C57BL/6J male mice were injected with 300 mg/kg APAP to establish an AILI model, and si-Cyp2e1 LNPs were administered via the tail vein. The results showed that the levels of serum alanine aminotransferase and aspartate aminotransferase were lower than those in APAP mice after treatment with si-Cyp2e1 LNPs immediately. Moreover, si-Cyp2e1 LNPs significantly inhibited liver necrosis and oxidative stress in APAP mice. RNA sequencing revealed that si-Cyp2e1 LNPs exerted regulatory effects on pathways and genes related to peroxisome proliferator-activated receptor (PPAR). Consistent with this finding, we also proved that si-Cyp2e1 LNPs markedly regulated the expressions of genes involved in the PPAR signaling pathway (CYP4A, PPARα, FABP 1, and CD36) in APAP mice, as well as inflammatory factors (Il-6, Il-1β, and Tnf-α). These findings suggested that si-Cyp2e1 LNPs may alleviate APAP-induced oxidative stress and inflammation by regulating lipid metabolism via PPAR-related pathways.