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Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease

Ferroptosis is a recently recognized form of regulated cell death, characterized by iron-dependent accumulation of lipid peroxidation. Ample evidence has depicted that ferroptosis plays an essential role in the cause or consequence of human diseases, including cancer, neurodegenerative disease and a...

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Autores principales: Dai, Yue, Chen, Yuting, Mo, Dexiameng, Jin, Rui, Huang, Yi, Zhang, Le, Zhang, Cuntai, Gao, Hongyu, Yan, Qi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10480178/
https://www.ncbi.nlm.nih.gov/pubmed/37670055
http://dx.doi.org/10.1038/s42003-023-05272-5
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author Dai, Yue
Chen, Yuting
Mo, Dexiameng
Jin, Rui
Huang, Yi
Zhang, Le
Zhang, Cuntai
Gao, Hongyu
Yan, Qi
author_facet Dai, Yue
Chen, Yuting
Mo, Dexiameng
Jin, Rui
Huang, Yi
Zhang, Le
Zhang, Cuntai
Gao, Hongyu
Yan, Qi
author_sort Dai, Yue
collection PubMed
description Ferroptosis is a recently recognized form of regulated cell death, characterized by iron-dependent accumulation of lipid peroxidation. Ample evidence has depicted that ferroptosis plays an essential role in the cause or consequence of human diseases, including cancer, neurodegenerative disease and acute kidney injury. However, the exact role and underlying mechanism of ferroptosis in fibrotic kidney remain unknown. Acyl-CoA synthetase long-chain family member 4 (ACSL4) has been demonstrated as an essential component in ferroptosis execution by shaping lipid composition. In this study, we aim to discuss the potential role and underlying mechanism of ACSL4-mediated ferroptosis of tubular epithelial cells (TECs) during renal fibrosis. The unbiased gene expression studies showed that ACSL4 expression was tightly associated with decreased renal function and the progression of renal fibrosis. To explore the role of ACSL4 in fibrotic kidney, ACSL4 specific inhibitor rosiglitazone (ROSI) was used to disturb the high expression of ACSL4 in TECs induced by TGF-β, unilateral ureteral obstruction (UUO) and fatty acid (FA)-modeled mice in vivo, and ACSL4 siRNA was used to knockdown ACSL4 in TGF-β-induced HK2 cells in vitro. The results demonstrated that inhibition and knockdown of ACSL4 effectively attenuated the occurrence of ferroptosis in TECs and alleviated the interstitial fibrotic response. In addition, the expression of various profibrotic cytokines all decreased after ROSI-treated in vivo and in vitro. Further investigation showed that inhibition of ACSL4 obviously attenuates the progression of renal fibrosis by reducing the proferroptotic precursors arachidonic acid- and adrenic acid- containing phosphatidylethanolamine (AA-PE and AdA-PE). In conclusion, these results suggest ACSL4 is essential for tubular ferroptotic death during kidney fibrosis development and ACSL4 inhibition is a viable therapeutic approach to preventing fibrotic kidney diseases.
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spelling pubmed-104801782023-09-07 Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease Dai, Yue Chen, Yuting Mo, Dexiameng Jin, Rui Huang, Yi Zhang, Le Zhang, Cuntai Gao, Hongyu Yan, Qi Commun Biol Article Ferroptosis is a recently recognized form of regulated cell death, characterized by iron-dependent accumulation of lipid peroxidation. Ample evidence has depicted that ferroptosis plays an essential role in the cause or consequence of human diseases, including cancer, neurodegenerative disease and acute kidney injury. However, the exact role and underlying mechanism of ferroptosis in fibrotic kidney remain unknown. Acyl-CoA synthetase long-chain family member 4 (ACSL4) has been demonstrated as an essential component in ferroptosis execution by shaping lipid composition. In this study, we aim to discuss the potential role and underlying mechanism of ACSL4-mediated ferroptosis of tubular epithelial cells (TECs) during renal fibrosis. The unbiased gene expression studies showed that ACSL4 expression was tightly associated with decreased renal function and the progression of renal fibrosis. To explore the role of ACSL4 in fibrotic kidney, ACSL4 specific inhibitor rosiglitazone (ROSI) was used to disturb the high expression of ACSL4 in TECs induced by TGF-β, unilateral ureteral obstruction (UUO) and fatty acid (FA)-modeled mice in vivo, and ACSL4 siRNA was used to knockdown ACSL4 in TGF-β-induced HK2 cells in vitro. The results demonstrated that inhibition and knockdown of ACSL4 effectively attenuated the occurrence of ferroptosis in TECs and alleviated the interstitial fibrotic response. In addition, the expression of various profibrotic cytokines all decreased after ROSI-treated in vivo and in vitro. Further investigation showed that inhibition of ACSL4 obviously attenuates the progression of renal fibrosis by reducing the proferroptotic precursors arachidonic acid- and adrenic acid- containing phosphatidylethanolamine (AA-PE and AdA-PE). In conclusion, these results suggest ACSL4 is essential for tubular ferroptotic death during kidney fibrosis development and ACSL4 inhibition is a viable therapeutic approach to preventing fibrotic kidney diseases. Nature Publishing Group UK 2023-09-05 /pmc/articles/PMC10480178/ /pubmed/37670055 http://dx.doi.org/10.1038/s42003-023-05272-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Dai, Yue
Chen, Yuting
Mo, Dexiameng
Jin, Rui
Huang, Yi
Zhang, Le
Zhang, Cuntai
Gao, Hongyu
Yan, Qi
Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease
title Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease
title_full Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease
title_fullStr Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease
title_full_unstemmed Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease
title_short Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease
title_sort inhibition of acsl4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10480178/
https://www.ncbi.nlm.nih.gov/pubmed/37670055
http://dx.doi.org/10.1038/s42003-023-05272-5
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