Abstract
Demand for a cure of liver fibrosis is rising with its increasing morbidity and mortality. Therefore, it is an urgent issue to investigate its therapeutic candidates. Liver fibrosis progresses following ‘multi-hit’ processes involving hepatic stellate cells, macrophages, and hepatocytes. The NOD-like receptor protein 3 (NLRP3) inflammasome is emerging as a therapeutic target in liver fibrosis. Previous studies showed that the anti-rheumatic agent auranofin inhibits the NLRP3 inflammasome; thus, this study evaluates the antifibrotic effect of auranofin in vivo and explores the underlying molecular mechanism. The antifibrotic effect of auranofin is assessed in thioacetamide- and carbon tetrachloride-induced liver fibrosis models. Moreover, hepatic stellate cell (HSC), bone marrow-derived macrophage (BMDM), kupffer cell, and hepatocyte are used to examine the underlying mechanism of auranofin. Auranofin potently inhibits activation of the NLRP3 inflammasome in BMDM and kupffer cell. It also reduces the migration of HSC. The underlying molecular mechanism was inhibition of cystine-glutamate antiporter, system Xc. Auranofin inhibits system Xc activity and instantly induced oxidative burst, which mediated inhibition of the NLRP3 inflammasome in macrophages and HSCs. Therefore, to the best of our knowledge, we propose the use of auranofin as an anti-liver fibrotic agent.
Highlights
Demand for a cure of liver fibrosis is rising with its increasing morbidity and mortality
Liver fibrosis is characterized by a multi-hit process involving a complex interplay between hepatocytes and nonparenchymal cells, including macrophages and HSCs25
Auranofin is a therapeutic agent clinically approved for treatment of rheumatoid arthritis; it has been recently investigated for potential therapeutic applications in a wide range of diseases[28,29]
Summary
Demand for a cure of liver fibrosis is rising with its increasing morbidity and mortality. The NOD-like receptor protein 3 (NLRP3) inflammasome is emerging as a therapeutic target in liver fibrosis. Auranofin potently inhibits activation of the NLRP3 inflammasome in BMDM and kupffer cell. The underlying molecular mechanism was inhibition of cystine-glutamate antiporter, system Xc. Auranofin inhibits system Xc activity and instantly induced oxidative burst, which mediated inhibition of the NLRP3 inflammasome in macrophages and HSCs. to the best of our knowledge, we propose the use of auranofin as an anti-liver fibrotic agent. Hepatic fibrosis progresses through a “multi-hit” process involving death of hepatocytes, cytokine secretion from macrophages, and activation of hepatic stellate cells (HSCs)[5]. We show that auranofin inhibited the NLRP3 inflammasome by blocking the Xc antiporter system
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