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Sirtuin five knockdown induced the ferroptosis of hepatic stellate cells in hepatic fibrosis progression through de-succinylation modification of GPX4.

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Τίτλος: Sirtuin five knockdown induced the ferroptosis of hepatic stellate cells in hepatic fibrosis progression through de-succinylation modification of GPX4.
Συγγραφείς: Zhou J; College of Basic Medicine, Guiyang Healthcare Vocational University, Guiyang, Guizhou, China. Electronic address: zj18984813912@126.com., Zhang J; School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, China., Zheng S; College of Pharmacy, Guiyang Healthcare Vocational University, Guiyang, Guizhou, China., Zhu J; College of Pharmacy, Guiyang Healthcare Vocational University, Guiyang, Guizhou, China., Wang K; College of Basic Medicine, Guiyang Healthcare Vocational University, Guiyang, Guizhou, China., Guo X; College of Basic Medicine, Guiyang Healthcare Vocational University, Guiyang, Guizhou, China.
Πηγή: The Journal of biological chemistry [J Biol Chem] 2026 Sep; Vol. 302 (9), pp. 113366. Date of Electronic Publication: 2026 Jul 24.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
Imprint Name(s): Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
Ιατρικοί όροι (MeSH): Ferroptosis*/genetics , Liver Cirrhosis*/metabolism , Liver Cirrhosis*/pathology , Liver Cirrhosis*/chemically induced , Sirtuins*/metabolism , Sirtuins*/genetics , Sirtuins*/deficiency , Hepatic Stellate Cells*/metabolism , Hepatic Stellate Cells*/pathology , Phospholipid Hydroperoxide Glutathione Peroxidase*/metabolism , Gene Knockdown Techniques*, Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta1/pharmacology ; Animals ; Mice ; Humans ; Male ; Cell Line ; Mice, Inbred C57BL ; Disease Progression
Περίληψη: Hepatic fibrosis results from persistent pathological damage and repair following various chronic liver injuries. In this study, we explored the specific mechanism of sirtuin 5 (SIRT5) in the development of hepatic fibrosis. Transforming growth factor-beta 1 (TGF-β1)-treated LX-2 cells and CCl4-treated mice were used to establish hepatic fibrosis models in vitro and in vivo. Cell viability was assessed using the CCK-8 assay, and ferroptosis-related indicators were measured with commercial kits. Protein expression and succinylation levels were analyzed by Western blot. Liver tissue structure in fibrotic mice was evaluated using hematoxylin and eosin (H&E), Masson, and Sirius Red staining. SIRT5 expression and global succinylation levels were elevated in TGF-β1-treated LX-2 cells. Knockdown of SIRT5 reduced cell viability and glutathione (GSH) levels while increasing malondialdehyde (MDA), iron, and reactive oxygen species (ROS) levels in these cells. Furthermore, SIRT5 knockdown enhanced the succinylation of glutathione peroxidase 4 (GPX4) and decreased GPX4 protein stability and expression. In vivo experiments showed that SIRT5 knockdown ameliorated liver structure in fibrotic mice by targeting GPX4 expression. Our study demonstrates that SIRT5 knockdown induces ferroptosis in TGF-β1-treated LX-2 cells by decreasing GPX4 protein levels via desuccinylation.
(Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.)
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
Contributed Indexing: Keywords: GPX4; SIRT5; ferroptosis; hepatic fibrosis; succinylation
Substance Nomenclature: EC 3.5.1.- (Sirtuins)
EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
EC 1.11.1.9 (glutathione peroxidase 4, mouse)
0 (Reactive Oxygen Species)
0 (SIRT5 protein, mouse)
0 (Transforming Growth Factor beta1)
Entry Date(s): Date Created: 20260724 Date Completed: 20260922 Latest Revision: 20260922
Update Code: 20260923
PubMed Central ID: PMC13524596
DOI: 10.1016/j.jbc.2026.113366
PMID: 42497991
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1083-351X
DOI:10.1016/j.jbc.2026.113366