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.

Auranofin attenuates Schistosoma mansoni egg-induced liver granuloma and fibrosis in mice

“…Similarly, Hwangbo et al (2020) revealed that auranofin may have the potential to be a candidate for reducing the symptoms of non-alcoholic fatty liver disease by inhibiting the NLRP3 inflammasome (Hwangbo et al 2020). Auranofin was also shown by Kim et al (2021) to considerably slow the progression of fibrosis in a thioacetamide- or carbon tetrachloride-induced fibrotic liver (Kim et al 2021). Additionally, Kaufmann et al (2022) found that the production of pro-inflammatory and pro-fibrotic cytokines as well as the onset of liver inflammation and fibrosis depends on the activation of the NLRP3 inflammasome complex in myeloid cells (Kaufmann et al 2022).…”

“…shown by Kim et al (2021) to considerably slow the progression of fibrosis in a thioacetamide-or carbon tetrachloride-induced fibrotic liver (Kim et al 2021). Additionally, Kaufmann et al (2022) found that the production of pro-inflammatory and profibrotic cytokines as well as the onset of liver inflammation and fibrosis depends on the activation of the NLRP3 inflammasome complex in myeloid cells (Kaufmann et al 2022).…”

“…Masson's trichrome staining showed that auranofin reduced fibrosis and significantly improved gross hepatic morphology with a lower percentage of collagen in the late-treated group. Since there are no first-line treatments for liver fibrosis, a study's findings demonstrate auranofin therapeutic efficacy in liver fibrosis (Kim et al 2021).…”

“…It was found that auranofin reduced worm burden in S. mansoni- infected mice likely through inhibition of Thioredoxin glutathione reductase (TGR) (Kuntz et al 2007), and it has in vitro worm-killing action (Kim et al 2019). Two experimental liver fibrosis models were used to evaluate the possibility of using auranofin clinically to treat liver fibrosis (Kim et al 2021); however, the liver fibrosis caused by S. mansoni differs from other models of liver fibrosis in that the host is impacted by the stimulation of the eggs and the growth of the worm. Therefore, we hypothesized that auranofin’s anti-inflammatory effects, activating macrophage autophagy and preventing inflammasome activation, will alleviate S. mansoni egg-induced liver granuloma and later development of hepatic fibrosis.…”

Correspondence on Letter regarding “Auranofin attenuates hepatic steatosis and fibrosis in nonalcoholic fatty liver disease via NRF2 and NF-κB signaling pathways”

“…Auranofin has been shown to induce ferroptosis via the GSH/GPX axis. Additionally, our previous study indicated that auranofin inhibited system Xc – in macrophages and the NOD-like receptor family pyrin domain containing 3 inflammasome in inflammatory cells [ 12 ]. However, ferroptosis can simultaneously induce iron-dependent lipid peroxidation.…”