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Auranofin prevents liver fibrosis by system Xc-mediated inhibition of NLRP3 inflammasome.

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.

SUBMITTER: Kim HY

PROVIDER: S-EPMC8245406 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Auranofin prevents liver fibrosis by system Xc-mediated inhibition of NLRP3 inflammasome.

Kim Hyun Young HY Choi Young Jae YJ Kim Sang Kyum SK Kim Hyunsung H Jun Dae Won DW Yoon Kyungrok K Kim Nayoun N Hwang Jungwook J Kim Young-Mi YM Lim Sung Chul SC Kang Keon Wook KW

Communications biology 20210630 1

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, ...[more]

PMID: 34193972

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Auranofin prevents liver fibrosis by system Xc-mediated inhibition of NLRP3 inflammasome.

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Auranofin prevents liver fibrosis by system Xc-mediated inhibition of NLRP3 inflammasome.

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