Dihydroartemisinin alleviates hepatic fibrosis through inducing ferroptosis in hepatic stellate cells

Zhang, Zili; Wang, Xian; Wang, Zilong; Zhang, Zhiyue; Cao, Yashi; Wei, Zonghui; Chen, Anping; Zhang, Feng; Zheng, Shizhong

doi:10.1002/biof.1764

Cited by 33 publications

(33 citation statements)

References 36 publications

(135 reference statements)

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“…Previous researches have confirmed that DHA can also result in iron homeostasis imbalance in cancer cells, which in turn leads to ferroptosis [ 18 ]. In addition, previous studies by our team have confirmed that DHA can induce ferroptosis of hepatic stellate cells and reverse the development of hepatic fibrosis [ 19 ]. Here, we will discuss whether DHA can induce HCC ferroptosis and exert an antitumor effect by regulating the formation of the PEBP1/15-LO complex.…”

Section: Introductionmentioning

confidence: 72%

“…Studies have shown that artemisinin and its derivatives can effectively induce tumor cell ferroptosis [ 24 , 25 ]. In addition, DHA was recently shown to induce ferroptosis in hepatic stellate cells [ 19 ]. Therefore, we hypothesized that DHA exerted antitumor activity in this study mainly by regulating HCC ferroptosis.…”

Section: Resultsmentioning

confidence: 99%

“…However, DHA-induced ferroptosis in hepatoma cells has not been reported. Our team has previously proved that DHA can induce ferroptosis of hepatic stellate cells [ 19 ]. Based on this, this research innovatively proposed that DHA could induce ferroptosis of HCC cells to exert antitumor effects.…”

Section: Discussionmentioning

confidence: 99%

“…As previously described [ 23 ], DHA was dissolved in 10% DMSO and 5% Kolliphor HS 15 in PBS and injected intraperitoneally once daily for about 3 weeks when the tumor grew to 150 mm 3 . All the mice were divided into six groups (four or five animals per group), including model group, DHA low, medium- and high-dose group [ 19 ], PEBP1 interference group, and DHA administration with PEBP1 interference group. Mice were anaesthetized by injecting pentobarbital (50 mg/kg) and then sacrificed at the end of the experiment.…”

Section: Methodsmentioning

confidence: 99%

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Dihydroartemisinin Induces Ferroptosis in HCC by Promoting the Formation of PEBP1/15‐LO

Zhao

Jin³

et al. 2021

Oxidative Medicine and Cellular Longevity

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Relevant researches have recognized the vital role of inducing ferroptosis in the treatment of tumor. The latest findings indicate that PEBP1/15-LO can play an essential role in the process of cell death. However, its role in regulating ferroptosis in hepatocellular carcinoma (simplified by HCC) remains unclear. The previous research of our team has proved that DHA can induce ferroptosis of hepatic stellate cells. In this study, we found that DHA could also induce ferroptosis in HCC cells. Interestingly, DHA induced ferroptosis by promoting the formation of PEBP1/15-LO and promoting cell membrane lipid peroxidation. In addition, we also found that DHA had no obvious regulatory effect on 15-LO, but it could promote PEBP1 protein expression. Importantly, we discovered the upregulation of PEBP1 induced by DHA was related to the inhibition of its ubiquitination degradation. In vivo experiments have also obtained consistent results that DHA can inhibit tumor growth and affect the expression of ferroptosis markers in tumor tissues, which would be partially offset by interference with PEBP1.

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Section: Introductionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Dihydroartemisinin Induces Ferroptosis in HCC by Promoting the Formation of PEBP1/15‐LO

Zhao

Jin³

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Activation of STAT3 signaling was also shown to promote fibrosis in pulmonary, cardiac, and liver disease ( 64 – 66 ). Research indicated that DHA can prevent fibrogenesis by inhibiting the activation of STAT3 in in vitro and in vivo models of liver fibrosis, skin fibrosis, systemic sclerosis, and pulmonary vascular remodeling, among others ( 67 – 69 ). Our study provides also first-time evidence that DHA restrains GO-related fibrosis by inhibiting the phosphorylation of STAT3 in OFs.…”

Section: Discussionmentioning

confidence: 99%

Dihydroartemisinin Exerts Antifibrotic and Anti-Inflammatory Effects in Graves’ Ophthalmopathy by Targeting Orbital Fibroblasts

et al. 2022

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Graves’ ophthalmopathy (GO) is a common orbital disease that threatens visual function and appearance. Orbital fibroblasts (OFs) are considered key target and effector cells in GO. In addition, hyaluronan (HA) production, inflammation, and orbital fibrosis are intimately linked to the pathogenesis of GO. In this study, we explored the therapeutic effects of dihydroartemisinin (DHA), an antimalarial drug, on GO-derived, primary OFs. CCK8 and EdU assays were applied to evaluate the antiproliferative effect of DHA on OFs. Wound healing assays were conducted to assess OF migration capacity, while qRT-PCR, western blotting, ELISA, and immunofluorescence were used to determine the expression of fibrosis-related and pro-inflammatory markers in these cells. Moreover, RNA sequencing was conducted to identify differentially expressed genes (DEGs) in DHA-treated OFs, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs was performed to explore potential mechanisms mediating the antifibrotic effect of DHA on GO-derived OFs. Results showed that DHA dose-dependently inhibited OF proliferation and downregulated, at the mRNA and protein levels, TGF-β1-induced expression of fibrosis markers, including alpha smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF). Furthermore, DHA inhibited TGF-β1 induced phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3), which suggested that DHA exerted antifibrotic effects via suppression of the ERK and STAT3 signaling pathways. In addition, DHA suppressed the expression of pro-inflammatory cytokines and chemokines, including IL-6, IL-8, CXCL-1, MCP-1, and ICAM-1, and attenuated HA production induced by IL-1β in GO-derived OFs. In conclusion, our study provides first-time evidence that DHA may significantly alleviate pathogenic manifestations of GO by inhibiting proliferation, fibrosis- and inflammation-related gene expression, and HA production in OFs. These data suggest that DHA may be a promising candidate drug for treatment of GO.

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LncRNA FRMD6‐AS1/miR‐491‐5p/USP13 pathway attenuated ferroptosis and contributed to liver fibrosis

Li,

Zou,

Jin

et al. 2024

Environmental Toxicology

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Liver fibrosis is an invertible pathophysiologic process featured by excessive accumulation of extracellular matrix (ECM) which injures liver cells and activates hepatic stellate cells (HSCs). Besides, inducing ferroptosis in activated HSCs can alleviate liver fibrosis. LncRNAs modulate ferroptosis in activated HSCs and ECM deposition in liver fibrosis. However, the role of lncRNA FRMD6‐AS1 in liver fibrosis is not discovered. In this study, lncRNA FRMD6‐AS1 was dramatically up‐regulated in activated HSCs. Knockdown of FRMD6‐AS1 markedly increased iron ion, ROS and MDA levels, decreased GSH level, SLC7A11 and GPX4 protein expressions in activated HSCs. In addition, HSCs activation markers α‐SMA and COL1α1 expressions were up‐regulated in activated HSCs; knockdown of FRMD6‐AS1 markedly down‐regulated α‐SMA and COL1α1 expressions in HSCs. Besides, lncRNA FRMD6‐AS1 could interact with miR‐491‐5p, and negatively modulate miR‐491‐5p expression. USP13 was a target of miR‐491‐5p, and could be negatively modulated by miR‐491‐5p. Moreover, FRMD6‐AS1 knockdown increased iron ion and ROS levels, decreased SLC7A11 and GPX4 protein expressions, facilitated HSCs viability, and up‐regulated α‐SMA and COL1α1 expressions via miR‐491‐5p/USP13 pathway. Finally, FRMD6‐AS1 knockdown restored liver tissue structure and abrogated fibrosis in livers in a CCL4 liver fibrosis mouse model. Hence, lncRNA FRMD6‐AS1/miR‐491‐5p/USP13 pathway repressed ferroptosis, promoted ECM deposition and facilitated liver fibrosis in vitro and in vivo models.

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Dihydroartemisinin alleviates hepatic fibrosis through inducing ferroptosis in hepatic stellate cells

Abstract: Targeting the elimination of activated hepatic stellate cells (HSCs) and blocking excessive deposition of extracellular matrix are recognized as an effective strategy for the treatment of hepatic fibrosis. As a newly discovered

Cited by 33 publications

References 36 publications

Dihydroartemisinin Induces Ferroptosis in HCC by Promoting the Formation of PEBP1/15‐LO

Dihydroartemisinin Induces Ferroptosis in HCC by Promoting the Formation of PEBP1/15‐LO

Dihydroartemisinin Exerts Antifibrotic and Anti-Inflammatory Effects in Graves’ Ophthalmopathy by Targeting Orbital Fibroblasts

LncRNA FRMD6‐AS1/miR‐491‐5p/USP13 pathway attenuated ferroptosis and contributed to liver fibrosis

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