Clin Mol Hepatol > Volume 29(1); 2023 > Article
Lee and Jun: Correspondence on Letter regarding “Auranofin attenuates hepatic steatosis and fibrosis in nonalcoholic fatty liver disease via NRF2 and NF-κB signaling pathways”
Dear Editor,
We appreciate your interest in our study. As pointed out by Liu and Chen [1], non-alcoholic fatty liver disease (NAFLD) has a broad heterogeneous spectrum and a diverse pathophysiology [2-8]. The relationship between auranofin-induced ferroptosis and NAFLD is somewhat complex [9]. It depends on the cell type and disease condition. Ferroptosis is associated with the pathogenesis of NAFLD, and inhibiting ferroptosis can inhibit necrotic cell death, inflammatory cell infiltration, and inflammatory cytokine expression in early-stage NAFLD [9]. However, in late-stage NAFLD and hepatocellular carcinoma, inhibition of ferroptosis is associated with disease progression [10,11]. In previous studies, the expression of glutathione peroxidase (GPX) 4, which protects cells against membrane lipid peroxidation, has been shown to vary according to the severity of NAFLD. In addition, the association between ferroptosis and NAFLD has been observed to vary depending on the animal model of NAFLD. This indicates that ferroptosis may play various roles at different stages of NAFLD. System Xc and NAFLD also share a complex relationship. A large body of evidence suggests that auranofin induces ferroptosis via the cystineglutamate antiporter system Xc. 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. Yang et al. [13] demonstrated that auranofin at high doses (25 mg/kg) induces ferroptosis but causes lipid peroxidation by inhibiting thioredoxin reductase activity. In conclusion, it is evident that auranofin acts as an inhibitor of system Xc. However, ferroptosis induced by system Xc inhibitors appears to play a different role in disease progression depending on the liver cell type and severity of NAFLD. Therefore, for the clinical application of auranofin, it is important to select a target population that is anticipated to have a positive therapeutic effect.

FOOTNOTES

Authors’ contribution
All authors contributed in conception of the work and drafting of the article. All authors provided final approval of the version to be published.
Conflicts of Interest
The authors have no conflicts to disclose.

Abbreviations

GPX
glutathione peroxidase
NAFLD
non-alcoholic fatty liver disease

REFERENCES

1. Liu Y, Chen M. Repurposing auranofin in nonalcoholic fatty liver disease still requires further evidence. Clin Mol Hepatol 2023;29:163-164.
crossref pdf
2. Kim HY. Recent advances in nonalcoholic fatty liver disease metabolomics. Clin Mol Hepatol 2021;27:553-559.
crossref pmid pmc pdf
3. Nam HH, Jun DW, Jeon HJ, Lee JS, Saeed WK, Kim EK. Osthol attenuates hepatic steatosis via decreased triglyceride synthesis not by insulin resistance. World J Gastroenterology 2014;20:11753-11761.
crossref
4. Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH, et al. KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021;27:363-401.
crossref pmid pmc pdf
5. Ting YW, Kong AS, Zain SM, Chan WK, Tan HL, Mohamed Z, et al. Loss-of-function HSD17B13 variants, non-alcoholic steatohepatitis and adverse liver outcomes: results from a multi-ethnic Asian cohort. Clin Mol Hepatol 2021;27:486-498.
crossref pmid pmc pdf
6. Ikejima K, Kon K, Yamashina S. Nonalcoholic fatty liver disease and alcohol-related liver disease: from clinical aspects to pathophysiological insights. Clin Mol Hepatol 2020;26:728-735.
crossref pmid pmc pdf
7. Soon G, Wee A. Updates in the quantitative assessment of liver fibrosis for nonalcoholic fatty liver disease: histological perspective. Clin Mol Hepatol 2021;27:44-57.
crossref pmid pdf
8. Kim KS, Lee BW. Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease. Clin Mol Hepatol 2020;26:430-443.
crossref pmid pmc pdf
9. Wang S, Liu Z, Geng J, Li L, Feng X. An overview of ferroptosis in non-alcoholic fatty liver disease. Biomed Pharmacother 2022;153:113374.
crossref pmid
10. Chen J, Li X, Ge C, Min J, Wang F. The multifaceted role of ferroptosis in liver disease. Cell Death Differ 2022;29:467-480.
crossref pmid pmc pdf
11. Kumar R, Goh BG, Kam JW, Chang PE, Tan CK. Comparisons between non-alcoholic steatohepatitis and alcohol-related hepatocellular carcinoma. Clin Mol Hepatol 2020;26:196-208.
crossref pmid pmc pdf
12. Kim HY, Choi YJ, Kim SK, Kim H, Jun DW, Yoon K, et al. Auranofin prevents liver fibrosis by system Xc-mediated inhibition of NLRP3 inflammasome. Commun Biol 2021;4:824.
crossref pmid pmc pdf
13. Yang L, Wang H, Yang X, Wu Q, An P, Jin X, et al. Auranofin mitigates systemic iron overload and induces ferroptosis via distinct mechanisms. Signal Transduct Target Ther 2020;5:138.
crossref pmid pmc pdf

Editorial Office
The Korean Association for the Study of the Liver
Room A1210, 53 Mapo-daero(MapoTrapalace, Dowha-dong), Mapo-gu, Seoul, 04158, Korea
TEL: +82-2-703-0051   FAX: +82-2-703-0071    E-mail: kasl@kams.or.kr
Copyright © The Korean Association for the Study of the Liver.         
COUNTER
TODAY : 1610
TOTAL : 1794585
Close layer