Iron regulatory protein 2 is required for artemether -mediated anti-hepatic fibrosis through ferroptosis pathway

Li, Yujia; Jin, Chen; Shen, Min; Wang, Zhenyi; Tan, Shanzhong; Chen, Anping; Wang, Shijun; Shao, Jiangjuan; Zhang, Feng; Zhang, Zili; Zheng, Shizhong

doi:10.1016/j.freeradbiomed.2020.09.008

Cited by 62 publications

(43 citation statements)

References 28 publications

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“…Further recognition of ferroptosis in the development of liver fibrosis has brought new perspectives for diagnosis and treatment. Attractively, Li et al recently reported that artemether-induced ferroptosis alleviates liver fibrosis via IRP2/Iron/ROS axis [ 34 ]. Furthermore, Kuo et al found that chrysophanol attenuates liver fibrosis induced by hepatitis B virus X protein by regulating HSC ferroptosis [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells

et al. 2021

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Ferroptosis is a recently identified non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. However, the underlying exact mechanisms remain poorly understood. Here, we report that the total levels of N 6 -methyladenosine (m 6 A) modification are evidently increased upon exposure to ferroptosis-inducing compounds due to the upregulation of methylase METTL4 and the downregulation of demethylase FTO. Interestingly, RNA-seq shows that m 6 A modification appears to trigger autophagy activation by stabilizing BECN1 mRNA, which may be the potential mechanism for m 6 A modification-enhanced HSC ferroptosis. Importantly, YTHDF1 is identified as a key m 6 A reader protein for BECN1 mRNA stability, and knockdown of YTHDF1 could prevent BECN1 plasmid-induced HSC ferroptosis. Noteworthy, YTHDF1 promotes BECN1 mRNA stability and autophagy activation via recognizing the m 6 A binding site within BECN1 coding regions. In mice, erastin treatment alleviates liver fibrosis by inducing HSC ferroptosis. HSC-specific inhibition of m 6 A modification could impair erastin-induced HSC ferroptosis in murine liver fibrosis. Moreover, we retrospectively analyzed the effect of sorafenib on HSC ferroptosis and m 6 A modification in advanced fibrotic patients with hepatocellular carcinoma (HCC) receiving sorafenib monotherapy. Attractively, the m 6 A modification upregulation, autophagy activation, and ferroptosis induction occur in human HSCs. Overall, these findings reveal novel signaling pathways and molecular mechanisms of ferroptosis, and also identify m 6 A modification-dependent ferroptosis as a potential target for the treatment of liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells

et al. 2021

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“…Previous study on collagen-induced arthritis rats showed that compared with intraperitoneally injection of MTX, intramuscularly administration of ART (3 mg/kg/day) similarly reduced in ammation and bone erosion in the paws with greater tolerability [42]. In another study, intraperitoneal injection of ART (10 mg/kg/day) showed anti-brosis effect in hepatic brosis mice model [43]. HCQ has antiin ammatory effect on lymphocytes by inhibiting lysosomal and autophagosome functions [44].…”

Section: Discussionmentioning

confidence: 98%

Artemether Targets Raptor-Induced Actin Polymerization and Suppresses Migration of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

Jing

Wang

et al. 2021

Preprint

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Background: Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) may cause articular damage as a result of its aggressive features including direct adhesion and invasion of surface cartilage in joints. Artemether (ART), one of the artemisinin derivatives with antimalarial properties, showed inhibitory effect on inflammation and destruction of joints in collagen-induced arthritis rats, which might be applied in RA treatment. However, whether ART has effects on the aggressive properties of human RA-FLS remains unexplored. Methods: Synovium was obtained from patients with active RA (n=18) and FLS were isolated in vitro. RA-FLS were subjected to cell migration, invasion assays, live-cell imaging analysis and Rho GTPase activation assay after ART treatment. To identify the therapeutic target of ART, key signaling molecules of PI3K/Akt, AMPK, MAPK, NF-κB and mTOR pathways from RA-FLS were examined by Western Blot after ART treatment. Raptor was knockdown or overexpressed by siRNA or lentivirus transfection to reveal its role on regulating the aggressive properties of RA-FLS.Results: ART treatment significantly suppressed the transwell migration and invasion of synovial FLS from RA patients. Time-lapse microscopy revealed that ART treatment reduced random migration velocity of RA-FLS, as well as the directional persistence. ART also impaired the formation of filopodia and lamellipodia in RA-FLS. Further mechanism investigation showed that ART reduced the protein level of Raptor, a critical component of the mTOR pathway, and its downstream target 4E-BP1. It also inhibited the activation of Rho GTPases and the expression of actin binding proteins, including Profilin 1 and p-Cofilin. Raptor overexpression could reverse the anti-migration and anti-invasion effects of ART on RA-FLS as well as the suppression of Rho GTPases activation and the expression of actin binding proteins. Conclusion: ART can inhibit migration of RA-FLS by blocking Raptor-induced actin polymerization. ART might be a potential agent targeting FLS in RA treatment.

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“…Iron can form both ferric (Fe 3+ ) and ferrous (Fe 2+ ) ions. After absorbed from duodenal villous epithelial cells from the diet, extracellular iron can be imported by transferrin and its carrier protein transferrin receptor (TFR) 8 . TFR is sorted to endosomes after binding with transferrin, where the binding of transferrin and TFR as well as that of iron and transferrin are dissolved in acidic environment.…”

Section: Overview Of Ferroptosismentioning

confidence: 99%

Ferroptosis and Liver Fibrosis

Pan¹,

Luo²,

Xia³

et al. 2021

Int. J. Med. Sci.

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Ferroptosis is an iron-dependent form of regulated cell death, which is characterized by a large amount of lipid peroxide accumulation and the imbalance of redox state in cells. Ferroptosis is usually accompanied with the dysfunction of lipid repair enzyme (glutathione peroxidase 4, GPX4), large masses of iron accumulation and lipid peroxidation of polyunsaturated fatty acids (PUFAs). Ferroptosis is related to several signaling pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion and p53 and Keap1/Nrf2 signaling pathways. A number of studies have indicated that ferroptosis is closely associated with acute renal failure, tumor, ischemia and reperfusion injury, neurodegenerative diseases and liver fibrosis. Liver fibrosis, which has long been a global health problem, still lacks effective treatment till now, and the discovery of ferroptosis provides a new insight into addressing this issue.

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Iron regulatory protein 2 is required for artemether -mediated anti-hepatic fibrosis through ferroptosis pathway

Cited by 62 publications

References 28 publications

N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells

N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells

Artemether Targets Raptor-Induced Actin Polymerization and Suppresses Migration of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

Ferroptosis and Liver Fibrosis

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