GAMG alleviates liver fibrosis through inducing ferroptosis in inflammatory macrophages via the IRF1/SLC7A11 signaling pathway

The activation of inflammatory macrophages plays a pivotal role in the development of liver fibrosis (LF). Ferroptosis contributes to the clearance of inflammatory macrophages and the release of profibrotic factors. Glycyrrhetic Acid 3-O-Mono-β-d-glucuronide (GAMG) is a natural compound, the potenti...

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Main Authors: Qing Pang, Shuai Zhou, Yong Wang, Hongtao Pan, Zhixin Wang, Xilaing Qin, Chao Zhu, Shilei Chen, Huichun Liu, Xiaosi Hu, Hao Jin
Format: Article
Language:English
Published: Elsevier 2025-03-01
Series:Redox Biology
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Online Access:http://www.sciencedirect.com/science/article/pii/S2213231725000229
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author Qing Pang
Shuai Zhou
Yong Wang
Hongtao Pan
Zhixin Wang
Xilaing Qin
Chao Zhu
Shilei Chen
Huichun Liu
Xiaosi Hu
Hao Jin
author_facet Qing Pang
Shuai Zhou
Yong Wang
Hongtao Pan
Zhixin Wang
Xilaing Qin
Chao Zhu
Shilei Chen
Huichun Liu
Xiaosi Hu
Hao Jin
author_sort Qing Pang
collection DOAJ
description The activation of inflammatory macrophages plays a pivotal role in the development of liver fibrosis (LF). Ferroptosis contributes to the clearance of inflammatory macrophages and the release of profibrotic factors. Glycyrrhetic Acid 3-O-Mono-β-d-glucuronide (GAMG) is a natural compound, the potential role of which on LF remains uncertain. In this study, GAMG treatment significantly reduced hepatocyte steatosis, fibroplasia, inflammatory cell infiltration, and collagen fiber deposition in LF mice. In addition, GAMG remarkably decreased the content of collagen protein and improved liver function indicators. Single-cell RNA sequencing revealed that GAMG significantly affected the changes of macrophage subsets in LF, and Funrich analysis identified IRF1 as a key transcription factor regulating the macrophage genome. IRF1 was significantly increased while ferroptosis related SLC7A11 was significantly down-regulated in GAMG treated inflammatory macrophages. Mass spectrometry metabolomics analysis showed that GAMG significantly affected metabolites associated with LF. In vivo and in vitro experiments further verified that GAMG induced ferroptosis of inflammatory macrophages through the IRF1/SLC7A11 axis, and ultimately alleviated LF. Therefore, GAMG induces ferroptosis of inflammatory macrophages by activating the IRF1/SLC7A11 axis, which provides a new strategy for the treatment of LF.
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spelling doaj-art-5232dc4b5a99495bb68721ff0d7ccccc2025-02-05T04:31:59ZengElsevierRedox Biology2213-23172025-03-0180103509GAMG alleviates liver fibrosis through inducing ferroptosis in inflammatory macrophages via the IRF1/SLC7A11 signaling pathwayQing Pang0Shuai Zhou1Yong Wang2Hongtao Pan3Zhixin Wang4Xilaing Qin5Chao Zhu6Shilei Chen7Huichun Liu8Xiaosi Hu9Hao Jin10Department of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, China; Anhui Province Key Laboratory of Occupational Health, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, ChinaDepartment of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, China; Anhui Province Key Laboratory of Occupational Health, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, ChinaDepartment of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, China; Anhui Province Key Laboratory of Occupational Health, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, ChinaDepartment of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, ChinaDepartment of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, ChinaDepartment of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, ChinaDepartment of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, ChinaDepartment of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, ChinaDepartment of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, China; Corresponding author.Department of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, China; Anhui Province Key Laboratory of Occupational Health, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, China; Corresponding author. Anhui Province Key Laboratory of Occupational Health, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, China.Department of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, China; Anhui Province Key Laboratory of Occupational Health, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, China; Corresponding author. Department of Hepatopancreatobiliary Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, 230041, China.The activation of inflammatory macrophages plays a pivotal role in the development of liver fibrosis (LF). Ferroptosis contributes to the clearance of inflammatory macrophages and the release of profibrotic factors. Glycyrrhetic Acid 3-O-Mono-β-d-glucuronide (GAMG) is a natural compound, the potential role of which on LF remains uncertain. In this study, GAMG treatment significantly reduced hepatocyte steatosis, fibroplasia, inflammatory cell infiltration, and collagen fiber deposition in LF mice. In addition, GAMG remarkably decreased the content of collagen protein and improved liver function indicators. Single-cell RNA sequencing revealed that GAMG significantly affected the changes of macrophage subsets in LF, and Funrich analysis identified IRF1 as a key transcription factor regulating the macrophage genome. IRF1 was significantly increased while ferroptosis related SLC7A11 was significantly down-regulated in GAMG treated inflammatory macrophages. Mass spectrometry metabolomics analysis showed that GAMG significantly affected metabolites associated with LF. In vivo and in vitro experiments further verified that GAMG induced ferroptosis of inflammatory macrophages through the IRF1/SLC7A11 axis, and ultimately alleviated LF. Therefore, GAMG induces ferroptosis of inflammatory macrophages by activating the IRF1/SLC7A11 axis, which provides a new strategy for the treatment of LF.http://www.sciencedirect.com/science/article/pii/S2213231725000229Glycyrrhetic acid 3-O-Mono-β-d-glucuronideLiver fibrosisFerroptosisInflammatory macrophagesIRF1SLC7A11
spellingShingle Qing Pang
Shuai Zhou
Yong Wang
Hongtao Pan
Zhixin Wang
Xilaing Qin
Chao Zhu
Shilei Chen
Huichun Liu
Xiaosi Hu
Hao Jin
GAMG alleviates liver fibrosis through inducing ferroptosis in inflammatory macrophages via the IRF1/SLC7A11 signaling pathway
Redox Biology
Glycyrrhetic acid 3-O-Mono-β-d-glucuronide
Liver fibrosis
Ferroptosis
Inflammatory macrophages
IRF1
SLC7A11
title GAMG alleviates liver fibrosis through inducing ferroptosis in inflammatory macrophages via the IRF1/SLC7A11 signaling pathway
title_full GAMG alleviates liver fibrosis through inducing ferroptosis in inflammatory macrophages via the IRF1/SLC7A11 signaling pathway
title_fullStr GAMG alleviates liver fibrosis through inducing ferroptosis in inflammatory macrophages via the IRF1/SLC7A11 signaling pathway
title_full_unstemmed GAMG alleviates liver fibrosis through inducing ferroptosis in inflammatory macrophages via the IRF1/SLC7A11 signaling pathway
title_short GAMG alleviates liver fibrosis through inducing ferroptosis in inflammatory macrophages via the IRF1/SLC7A11 signaling pathway
title_sort gamg alleviates liver fibrosis through inducing ferroptosis in inflammatory macrophages via the irf1 slc7a11 signaling pathway
topic Glycyrrhetic acid 3-O-Mono-β-d-glucuronide
Liver fibrosis
Ferroptosis
Inflammatory macrophages
IRF1
SLC7A11
url http://www.sciencedirect.com/science/article/pii/S2213231725000229
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