Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 21, 2024; 30(11): 1588-1608
Published online Mar 21, 2024. doi: 10.3748/wjg.v30.i11.1588
Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis
Xing-Nian Zhou, Quan Zhang, Hong Peng, Yu-Jie Qin, Yu-Hong Liu, Lu Wang, Ming-Liang Cheng, Xin-Hua Luo, Hong Li
Xing-Nian Zhou, Quan Zhang, Yu-Jie Qin, Yu-Hong Liu, Lu Wang, Ming-Liang Cheng, Hong Li, Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
Hong Peng, Xin-Hua Luo, Hong Li, Department of Infectious Diseases, Guizhou Provincial People's Hospital, Guiyang 550001, Guizhou Province, China
Co-first authors: Xing-Nian Zhou and Quan Zhang.
Co-corresponding authors: Hong Li and Xin-Hua Luo.
Author contributions: Li H and Luo XH designed the study; Zhou XN, Zhang Q, Peng H, Qin YJ, and Liu YH were involved in the data collection; Zhou XN, Qin YJ, and Liu YH analyzed the data; Zhou XN, Zhang Q, Luo XH, and Li H drafted the manuscript; all authors were involved in the critical review of the results and have contributed to, read, and approved the final manuscript. Zhou XN and Zhang Q contributed equally to this work as co-first authors. The reasons for designating Zhou XN and Zhang Q as co-first authors are threefold. First, the research was performed as a collaborative effort, and the designation of co-first authors authorship accurately reflects the distribution of responsibilities and burdens associated with the time and effort required to complete the study and the resultant paper. Zhou XN and Zhang Q co-designed this study and worked together to explore the feasibility, innovativeness, and scientific validity of this study. Second, Zhou XN and Zhang Q worked together to complete the cell and animal parts of this study. In the process of the study, we encountered heavy problems, but we did not abandon each other or give up the study, but inspired and promoted each other. Without each other, we would not have been able to complete the study successfully. Third, Zhou XN and Zhang Q wrote the paper together. We collected and analysed the data, and then plotted them into graphs. We reviewed the literature and learnt from each other, thus successfully completing this paper. In summary, we believe that designating Zhou XN and Zhang Q as co-first authors is fitting for our manuscript as it accurately reflects our team's collaborative spirit, equal contributions, and diversity. Luo XH and Li H contributed equally to this work as co-corresponding authors. Three aspects are described here to illustrate this. First, Luo XH and Li H jointly designed the study and completed the pilot experiments, which laid a solid foundation for the later experiments. Second, Luo XH and Li H worked together to help and solve the problems encountered during the study, thus facilitating the process of the study and finally completing it. When we encountered difficulties in our study and stopped moving forward, Luo XH and Li H provided us with valuable advice and research direction. When we wanted to give up, Luo XH and Li H inspired and motivated us. Under the leadership of Luo XH and Li H, we successfully achieved the current academic results. Third, Luo XH and Li H revised the current manuscript together, and Luo XH and Li H guided the framework structure of the paper. The paper could only be completed successfully under the tutelage of Luo XH and Li H. Luo XH and Li H played the roles of supervising, guiding, clearing doubts, and preaching throughout the study process.
Supported by National Natural Science Foundation of China, No. 82060123; Doctoral Start-up Fund of Affiliated Hospital of Guizhou Medical University, No. gysybsky-2021-28; Fund Project of Guizhou Provincial Science and Technology Department, No. [2020]1Y299; and Guizhou Provincial Health Commission, No. gzwjk2019-1-082.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Affiliated Hospital of Guizhou Medical University.
Informed consent statement: All study participants or their legal guardian provided informed written consent about personal and medical data collection prior to study enrolment.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Affiliated Hospital of Guizhou Medical University.
Conflict-of-interest statement: We have no financial relationships to disclose.
Data sharing statement: The data presented in this study are available from the corresponding author upon reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hong Li, PhD, Chief Physician, Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, No. 28 Guiyi Road, Guiyang 550004, Guizhou Province, China. 625062102@qq.com
Received: October 5, 2023
Peer-review started: October 5, 2023
First decision: December 6, 2023
Revised: December 20, 2023
Accepted: February 18, 2024
Article in press: February 18, 2024
Published online: March 21, 2024
Abstract
BACKGROUND

Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation.

AIM

To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms.

METHODS

This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing. C57BL/6 mice were also intraperitoneally pretreated with SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers and inhibitors and injected with lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- mice were used as an experimental group. Histological changes in liver tissue were monitored by hematoxylin and eosin staining. ALT, AST, glutathione, reactive oxygen species, and iron levels were measured using commercial kits. Ferroptosis- and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction. SIRT1, p53, and GSDMD were assessed by immunofluorescence analysis.

RESULTS

Serum AST and ALT levels were elevated in patients with ALF. SIRT1, solute carrier family 7a member 11 (SLC7A11), and GPX4 protein expression was decreased and acetylated p5, p53, GSDMD, and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein levels were elevated in human ALF liver tissue. In the p53 and ferroptosis inhibitor-treated and GSDMD-/- groups, serum interleukin (IL)-1β, tumour necrosis factor alpha, IL-6, IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated. In mice with GSDMD knockout, p53 was reduced, GPX4 was increased, and ferroptotic events (depletion of SLC7A11, elevation of ACSL4, and iron accumulation) were detected. In vitro, knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels, the cytostatic rate, and GSDMD expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group, accompanied by reduced p53, GSDMD, and ACSL4, and increased SLC7A11 and GPX4. Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalN-induced in vitro and in vivo models.

CONCLUSION

SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Keywords: Silent information regulator sirtuin 1, Ferroptosis, Pyroptosis, p53/glutathione peroxidase 4/gasdermin D, Acute liver failure

Core Tip: In this study, we investigated the involvement of ferroptosis and pyroptosis in acute liver failure (ALF) using lipopolysaccharide/D-galactosamine-induced ALF model mice. Our results showed that silent information regulator sirtuin 1 activation alleviated ALF through p53/glutathione peroxidase 4/gasdermin D, which mediated the ferroptosis and pyroptosis crosstalk. Our study established a link between ferroptosis and pyroptosis and the upstream regulatory mechanisms. These results may lead to the identification of potential therapeutic targets for ALF.