Wogonoside attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis through SOCS1 / P53 / SLC7A11 pathway

Liu, Guofang; Wei, Can; Yuan, Siyu; Zhang, Zhe; Li, Jiahao; Zhang, Lijun; Wang, Guokai; Fang, Ling

doi:10.1002/ptr.7558

Title: Wogonoside attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis through SOCS1 / P53 / SLC7A11 pathway

Journal Article · Mon Jul 11 00:00:00 EDT 2022 · PTR. Phytotherapy research

DOI:https://doi.org/10.1002/ptr.7558· OSTI ID:1996266

Liu, Guofang ^[1]; Wei, Can ^[2]; Yuan, Siyu ^[3]; Zhang, Zhe ^[4]; Li, Jiahao ^[1]; Zhang, Lijun ^[4];

^[1];

^[5]

School of Pharmacy Anhui University of Chinese Medicine Hefei China
Department of Urology The Second People's Hospital of Hefei Hefei China
Department of Pharmacy The First Affiliated Hospital of Anhui Medical University Hefei China
School of Pharmacy Anhui Medical University Hefei China
Department of Pharmacy The First Affiliated Hospital of Anhui Medical University Hefei China, The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine Hefei China

Abstract Wogonoside (WG) is a flavonoid chemical component extracted from Scutellaria baicalensis, which exerts therapeutic effects on liver diseases. Ferroptosis, a novel form of programmed cell death, regulates diverse physiological/pathological processes. In this study, we attempted to investigate a novel mechanism by which WG mitigates liver fibrosis by inducing ferroptosis in hepatic stellate cells (HSCs). A CCl ₄ ‐induced mouse liver fibrosis model and a rat HSC line were employed for in vivo and in vitro experiments, both treated with WG. Firstly, the levels of the fibrotic markers α‐smooth muscle actin (α‐SMA) and α1(I)collagen (COL1α1) were effectively decreased by WG in CCl ₄ ‐induced mice and HSC‐T6 cells. Additionally, mitochondrial condensation and mitochondrial ridge breakage were observed in WG‐treated HSC‐T6 cells. Furthermore, ferroptotic events including depletion of SLC7A11, GPX4 and GSH, and accumulation of iron, ROS and MDA were discovered in WG‐treated HSC‐T6 cells. Intriguingly, these ferroptotic events did not appear in hepatocytes or macrophages. WG‐elicited HSC ferroptosis and ECM reduction were dramatically abrogated by ferrostatin‐1 (Fer‐1), a ferroptosis inhibitor. Importantly, our results confirm that SOCS1/P53/SLC7A11 is a signaling pathway which promotes WG attenuation of liver fibrosis. On the contrary, WG mitigated liver fibrosis and inducted HSC‐T6 cell ferroptosis were hindered by SOCS1 siRNA and pifithrin‐α (PFT‐α). These findings demonstrate that SOCS1/P53/SLC7A11‐mediated HSC ferroptosis is associated with WG alleviating liver fibrosis, which provides a new clue for the treatment of liver fibrosis.

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Sponsoring Organization:: USDOE

OSTI ID:: 1996266

Journal Information:: PTR. Phytotherapy research, Journal Name: PTR. Phytotherapy research Vol. 36 Journal Issue: 11; ISSN 0951-418X

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: FAO

Language:: English

References (55)

SOCS1 Links Cytokine Signaling to p53 and Senescence Calabrese, Viviane; Mallette, Frédérick A.; Deschênes-Simard, Xavier Molecular Cell, Vol. 36, Issue 5 https://doi.org/10.1016/j.molcel.2009.09.044	journal	December 2009
Legumain promotes tubular ferroptosis by facilitating chaperone-mediated autophagy of GPX4 in AKI Chen, Chuan’ai; Wang, Dekun; Yu, Yangyang Cell Death & Disease, Vol. 12, Issue 1 https://doi.org/10.1038/s41419-020-03362-4	journal	January 2021
SOCS1, a novel interaction partner of p53 controlling oncogene-induced senescence Mallette, Frédérick A.; Calabrese, Viviane; Ilangumaran, Subburaj Aging, Vol. 2, Issue 7 https://doi.org/10.18632/aging.100163	journal	June 2010
Ferroptosis: molecular mechanisms and health implications Tang, Daolin; Chen, Xin; Kang, Rui Cell Research, Vol. 31, Issue 2 https://doi.org/10.1038/s41422-020-00441-1	journal	December 2020
Mutant p53 Drives Pancreatic Cancer Metastasis through Cell-Autonomous PDGF Receptor β Signaling Weissmueller, Susann; Manchado, Eusebio; Saborowski, Michael Cell, Vol. 157, Issue 2 https://doi.org/10.1016/j.cell.2014.01.066	journal	April 2014
(+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis Wang, Min; Liu, Chun-Yu; Wang, Tian Cell Death & Disease, Vol. 11, Issue 9 https://doi.org/10.1038/s41419-020-02961-5	journal	September 2020
Wogonoside Shows Antifibrotic Effects in an Experimental Regression Model of Hepatic Fibrosis Wang, Qichao; Wen, Rui; Lin, Qinghua Digestive Diseases and Sciences, Vol. 60, Issue 11 https://doi.org/10.1007/s10620-015-3751-4	journal	July 2015
Ferroptosis: past, present and future Li, Jie; Cao, Feng; Yin, He-liang Cell Death & Disease, Vol. 11, Issue 2 https://doi.org/10.1038/s41419-020-2298-2	journal	February 2020
CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy Wang, Weimin; Green, Michael; Choi, Jae Eun Nature, Vol. 569, Issue 7755 https://doi.org/10.1038/s41586-019-1170-y	journal	May 2019
P53‐dependent induction of ferroptosis is required for artemether to alleviate carbon tetrachloride‐induced liver fibrosis and hepatic stellate cell activation Wang, Ling; Zhang, Zili; Li, Mengmeng IUBMB Life, Vol. 71, Issue 1 https://doi.org/10.1002/iub.1895	journal	October 2018
Phosphorylated STAT5 regulates p53 expression via BRCA1/BARD1-NPM1 and MDM2 Ren, Zhuo; Aerts, Joeri L.; Vandenplas, Hugo Cell Death & Disease, Vol. 7, Issue 12 https://doi.org/10.1038/cddis.2016.430	journal	December 2016
Kinetics of repression by modified p53 on the PDGF β-receptor promoter Yang, Weiwen; Wetterskog, Daniel; Matsumoto, Yoshiki International Journal of Cancer, Vol. 123, Issue 9 https://doi.org/10.1002/ijc.23735	journal	November 2008
NF-κB and AMPK/PI3K/Akt signaling pathways are involved in the protective effects ofPlatycodon grandiflorumsaponins against acetaminophen-induced acute hepatotoxicity in mice Leng, Jing; Wang, Zi; Fu, Cheng-lin Phytotherapy Research, Vol. 32, Issue 11 https://doi.org/10.1002/ptr.6160	journal	July 2018
RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells Zhang, Zili; Guo, Mei; Li, Yujia Autophagy, Vol. 16, Issue 8 https://doi.org/10.1080/15548627.2019.1687985	journal	November 2019
Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence Jin, H.; Lian, N.; Zhang, F. Cell Death & Disease, Vol. 7, Issue 4 https://doi.org/10.1038/cddis.2016.92	journal	April 2016
Molecular and cellular mechanisms of liver fibrosis and its regression Kisseleva, Tatiana; Brenner, David Nature Reviews Gastroenterology & Hepatology, Vol. 18, Issue 3 https://doi.org/10.1038/s41575-020-00372-7	journal	October 2020
Effects of flavonoids extracted from Scutellaria baicalensis Georgi on hemin–nitrite–H2O2 induced liver injury Zhao, Yuling; Li, Hailing; Gao, Zhonghong European Journal of Pharmacology, Vol. 536, Issue 1-2 https://doi.org/10.1016/j.ejphar.2006.02.045	journal	April 2006
Iron regulatory protein 2 is required for artemether -mediated anti-hepatic fibrosis through ferroptosis pathway Li, Yujia; Jin, Chun; Shen, Min Free Radical Biology and Medicine, Vol. 160 https://doi.org/10.1016/j.freeradbiomed.2020.09.008	journal	November 2020
SLC3A2 inhibits ferroptosis in laryngeal carcinoma via mTOR pathway Wu, Fangxing; Xiong, Gaoyun; Chen, Zejun Hereditas, Vol. 159, Issue 1 https://doi.org/10.1186/s41065-022-00225-0	journal	January 2022
Ursodesoxycholic acid alleviates liver fibrosis via proregeneration by activation of the ID1‐WNT2/HGF signaling pathway Dong, Xi; Luo, Yun; Lu, Shan Clinical and Translational Medicine, Vol. 11, Issue 2 https://doi.org/10.1002/ctm2.296	journal	January 2021
Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF‐1α/SLC7A11 pathway Yuan, Siyu; Wei, Can; Liu, Guofang Cell Proliferation, Vol. 55, Issue 1 https://doi.org/10.1111/cpr.13158	journal	November 2021
Protective mechanisms of wogonoside against Lipopolysaccharide/D-galactosamine-induced acute liver injury in mice Gao, Yuan-zheng; Zhao, Lian-feng; Ma, Jun European Journal of Pharmacology, Vol. 780 https://doi.org/10.1016/j.ejphar.2016.02.040	journal	June 2016
Wogonoside alleviates colitis by improving intestinal epithelial barrier function via the MLCK/pMLC2 pathway Huang, Shaowei; Fu, Yajun; Xu, Bo Phytomedicine, Vol. 68 https://doi.org/10.1016/j.phymed.2020.153179	journal	March 2020
Liver fibrosis and repair: immune regulation of wound healing in a solid organ Pellicoro, Antonella; Ramachandran, Prakash; Iredale, John P. Nature Reviews Immunology, Vol. 14, Issue 3 https://doi.org/10.1038/nri3623	journal	February 2014
Effects of wogonoside on the inflammatory response and oxidative stress in mice with nonalcoholic fatty liver disease Jiang, Guangyu; Chen, Dayin; Li, Wenpeng Pharmaceutical Biology, Vol. 58, Issue 1 https://doi.org/10.1080/13880209.2020.1845747	journal	January 2020
Ferroptosis, a new form of cell death: opportunities and challenges in cancer Mou, Yanhua; Wang, Jun; Wu, Jinchun Journal of Hematology & Oncology, Vol. 12, Issue 1 https://doi.org/10.1186/s13045-019-0720-y	journal	March 2019
Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells Zhang, Zili; Yao, Zhen; Wang, Ling Autophagy, Vol. 14, Issue 12 https://doi.org/10.1080/15548627.2018.1503146	journal	August 2018
A Novel Ferroptosis-related Gene Signature for Overall Survival Prediction in Patients with Hepatocellular Carcinoma Liang, Jie-ying; Wang, De-shen; Lin, Hao-cheng International Journal of Biological Sciences, Vol. 16, Issue 13 https://doi.org/10.7150/ijbs.45050	journal	January 2020
Wogonoside inhibits tumor growth and metastasis in endometrial cancer via ER stress-Hippo signaling axis Chen, Shaorong; Wu, Zhuna; Ke, Yumin Acta Biochimica et Biophysica Sinica, Vol. 51, Issue 11 https://doi.org/10.1093/abbs/gmz109	journal	November 2019
Mechanisms of Hepatic Fibrogenesis Friedman, Scott L. Gastroenterology, Vol. 134, Issue 6 https://doi.org/10.1053/j.gastro.2008.03.003	journal	May 2008
Ferroptosis as a p53-mediated activity during tumour suppression Jiang, Le; Kon, Ning; Li, Tongyuan Nature, Vol. 520, Issue 7545 https://doi.org/10.1038/nature14344	journal	March 2015
Differential Contributions of STAT5A and STAT5B to Stress Protection and Tyrosine Kinase Inhibitor Resistance of Chronic Myeloid Leukemia Stem/Progenitor Cells Casetti, Luana; Martin-Lannerée, Séverine; Najjar, Imen Cancer Research, Vol. 73, Issue 7 https://doi.org/10.1158/0008-5472.CAN-12-3955	journal	April 2013
Magnesium isoglycyrrhizinate ameliorates liver fibrosis and hepatic stellate cell activation by regulating ferroptosis signaling pathway Sui, Miao; Jiang, Xiaofei; Chen, Jun Biomedicine & Pharmacotherapy, Vol. 106 https://doi.org/10.1016/j.biopha.2018.06.060	journal	October 2018
Role of GPX4 in ferroptosis and its pharmacological implication Seibt, Tobias M.; Proneth, Bettina; Conrad, Marcus Free Radical Biology and Medicine, Vol. 133 https://doi.org/10.1016/j.freeradbiomed.2018.09.014	journal	March 2019
Negative regulation of the hepatic fibrogenic response by suppressor of cytokine signaling 1 Kandhi, Rajani; Bobbala, Diwakar; Yeganeh, Mehdi Cytokine, Vol. 82 https://doi.org/10.1016/j.cyto.2015.12.007	journal	June 2016
Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis Yu, Yingying; Jiang, Li; Wang, Hao Blood, Vol. 136, Issue 6 https://doi.org/10.1182/blood.2019002907	journal	August 2020
Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway Kong, Zhaoyan; Liu, Rong; Cheng, Yuanrong Biomedicine & Pharmacotherapy, Vol. 109 https://doi.org/10.1016/j.biopha.2018.11.030	journal	January 2019
The Medicinal Plant Pair Bupleurum chinense-Scutellaria baicalensis – Metabolomics and Metallomics Analysis in a Model for Alcoholic Liver Injury Dang, Zefang; Li, Qianhua; Sun, Shujun Frontiers in Pharmacology, Vol. 10 https://doi.org/10.3389/fphar.2019.00254	journal	March 2019
Chaperone-mediated autophagy is involved in the execution of ferroptosis Wu, Zheming; Geng, Yang; Lu, Xiaojuan Proceedings of the National Academy of Sciences, Vol. 116, Issue 8 https://doi.org/10.1073/pnas.1819728116	journal	February 2019
Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis via Synergistic Repression of SLC7A11 Lang, Xueting; Green, Michael D.; Wang, Weimin Cancer Discovery, Vol. 9, Issue 12 https://doi.org/10.1158/2159-8290.CD-19-0338	journal	December 2019
A family of cytokine-inducible inhibitors of signalling Starr, Robyn; Willson, Tracy A.; Viney, Elizabeth M. Nature, Vol. 387, Issue 6636 https://doi.org/10.1038/43206	journal	June 1997
Carvacrol alleviates liver fibrosis by inhibiting TRPM7 and modulating the MAPK signaling pathway Cai, Shiyi; Wu, Lijun; Yuan, Siyu European Journal of Pharmacology, Vol. 898 https://doi.org/10.1016/j.ejphar.2021.173982	journal	May 2021
p53 Down Regulates PDGF-Induced Formation of Circular Dorsal Ruffles in Rat Aortic Smooth Muscle Cells Payne, Laura J.; Eves, Robert L.; Jia, Lilly PLoS ONE, Vol. 9, Issue 9 https://doi.org/10.1371/journal.pone.0108257	journal	September 2014
TRPM7 channel regulates PDGF-BB-induced proliferation of hepatic stellate cells via PI3K and ERK pathways Fang, Ling; Zhan, Shuxiang; Huang, Cheng Toxicology and Applied Pharmacology, Vol. 272, Issue 3 https://doi.org/10.1016/j.taap.2013.08.009	journal	November 2013
GPX4 degradation via chaperone-mediated autophagy contributes to antimony-triggered neuronal ferroptosis Yu, Shali; Li, Zhijie; Zhang, Qin Ecotoxicology and Environmental Safety, Vol. 234 https://doi.org/10.1016/j.ecoenv.2022.113413	journal	April 2022
History, Heterogeneity, Developmental Biology, and Functions of Quiescent Hepatic Stellate Cells Geerts, Albert Seminars in Liver Disease, Vol. 21, Issue 03 https://doi.org/10.1055/s-2001-17550	journal	January 2001
SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes Saint-Germain, Emmanuelle; Mignacca, Lian; Vernier, Mathieu Aging, Vol. 9, Issue 10 https://doi.org/10.18632/aging.101306	journal	October 2017
Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs Su, Yanwei; Zhao, Bin; Zhou, Liangfu Cancer Letters, Vol. 483 https://doi.org/10.1016/j.canlet.2020.02.015	journal	July 2020
Immunosuppressant flavonoids from Scutellaria baicalensis Syafni, Nova; Devi, Seema; Zimmermann-Klemd, Amy M. Biomedicine & Pharmacotherapy, Vol. 144 https://doi.org/10.1016/j.biopha.2021.112326	journal	December 2021
Xiaozhang Tie Improves Intestinal Motility in Rats With Cirrhotic Ascites by Regulating the Stem Cell Factor/c-kit Pathway in Interstitial Cells of Cajal Zhao, Qiang; Xing, Feng; Tao, Yanyan Frontiers in Pharmacology, Vol. 11 https://doi.org/10.3389/fphar.2020.00001	journal	February 2020
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death Dixon, Scott J.; Lemberg, Kathryn M.; Lamprecht, Michael R. Cell, Vol. 149, Issue 5 https://doi.org/10.1016/j.cell.2012.03.042	journal	May 2012
Characterization of ferroptosis in murine models of hemochromatosis Wang, Hao; An, Peng; Xie, Enjun Hepatology, Vol. 66, Issue 2 https://doi.org/10.1002/hep.29117	journal	May 2017
Structural Biology of the Tumor Suppressor p53 Joerger, Andreas C.; Fersht, Alan R. Annual Review of Biochemistry, Vol. 77, Issue 1 https://doi.org/10.1146/annurev.biochem.77.060806.091238	journal	June 2008
Liver fibrosis Bataller, Ramón; Brenner, David A. Journal of Clinical Investigation, Vol. 115, Issue 2 https://doi.org/10.1172/JCI24282	journal	February 2005
Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis Ingold, Irina; Berndt, Carsten; Schmitt, Sabine Cell, Vol. 172, Issue 3 https://doi.org/10.1016/j.cell.2017.11.048	journal	January 2018

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