MafG/MYH9-LCN2 axis promotes liver fibrosis through inhibiting ferroptosis of hepatic stellate cells.

Autor: Deng Y; Department of Ultrasonic Imaging, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.; Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China., Lu L; Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.; Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China., Zhu D; Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China., Zhang H; Department of Ultrasonic Imaging, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.; Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China., Fu Y; Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China., Tan Y; Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China., Tan X; Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China., Guo M; Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China., Zhang Y; Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China., Yang H; Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Yang B; Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Liu T; Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. liuting818@csu.edu.cn., Chen Y; Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. yonghenc@163.com.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2024 Sep; Vol. 31 (9), pp. 1127-1139. Date of Electronic Publication: 2024 Jun 13.
DOI: 10.1038/s41418-024-01322-5
Abstrakt: Hepatic stellate cells (HSCs) secrete extracellular matrix for collagen deposition, contributing to liver fibrosis. Ferroptosis is a novel type of programmed cell death induced by iron overload-dependent lipid peroxidation. Regulation of ferroptosis in hepatic stellate cells (HSCs) may have therapeutic potential for liver fibrosis. Here, we found that Maf bZIP transcription factor G (MafG) was upregulated in human and murine liver fibrosis. Interestingly, MafG knockdown increased HSCs ferroptosis, while MafG overexpression conferred resistance of HSCs to ferroptosis. Mechanistically, MafG physically interacted with non-muscle myosin heavy chain IIa (MYH9) to transcriptionally activate lipocalin 2 (LCN2) expression, a known suppressor for ferroptosis. Site-directed mutations of MARE motif blocked the binding of MafG to LCN2 promoter. Re-expression of LCN2 in MafG knockdown HSCs restored resistance to ferroptosis. In bile duct ligation (BDL)-induced mice model, we found that treatment with erastin alleviated murine liver fibrosis by inducing HSC ferroptosis. HSC-specific knowdown MafG based on adeno-associated virus 6 (AAV-6) improved erastin-induced HSC ferroptosis and alleviation of liver fibrosis. Taken together, MafG inhibited HSCs ferroptosis to promote liver fibrosis through transcriptionally activating LCN2 expression. These results suggest that MafG/MYH9-LCN2 signaling pathway could be a novel targets for the treatment of liver fibrosis.
(© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)
Databáze: MEDLINE
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