The NLRP3 inhibitor and Nrf2 Agonist, RRx-001, Ameliorates Non-alcoholic Fatty Liver Disease in Rats

Abstract

Lead Author's Financial Disclosures EpicentRx. Study Funding EpicentRx Inc. Background/Synopsis The development and progression of non-alcoholic steatohepatitis (NASH), an increasingly prevalent disease for which no pharmacological therapy has been approved, is linked to oxidative stress, inflammation, and fibrosis of the liver. Here, we investigated the novel mechanism of RRx-001, an NLRP3 inhibitor and Nrf2 agonist, which is in Phase 3 clinical trials for the treatment of cancer, as a therapeutic option for ameliorating NASH in a diet-induced mice model. Objective/Purpose To investigate whether intraperitoneal administration of RRx-001 improved high-fat diet-induced NASH in rats. Methods Sprague-Dawley rats (6-weeks-old male; about 180g weight) were randomly divided into three groups, one subjected to normal diet (ND) and two groups in high-fat, atherogenic diet (HFD, 40 kcal % fat, 1.25% cholesterol, 0.5% sodium cholate) for 12 weeks. One of HFD groups was treated IP with (5 mg/kg of RRx-001 every other week) for the last 8 weeks before characterization. Several markers of inflammation and steatosis were evaluated. Results Every other week administrations of RRx-001 reduced hepatic steatosis scores, serum ALT and AST levels, and hepatic levels of cholesterol and triglycerides in rats fed a high-fat diet. These were correlated with the suppression of NLRP3 inflammasome activation by RRx-001 as evidenced by decreased levels of NLRP3, caspase-1, and IL-1β levels on ELISA. Conclusions The findings of this study demonstrate that RRx-001 reduced inflammation with an anti-lipidemic and anti-NASH effect mediated at least in part by inhibition of the NLRP3 pathway. Thus, targeting the NLRP3 inflammasome with RRx-001 may contribute to the prevention and treatment of NASH. EpicentRx.