Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis

doi:10.3748/wjg.v30.i11.1588

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World Journal of Gastroenterology

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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.

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
Processing time: 168 Days and 9.2 Hours

ARTICLE HIGHLIGHTS

Research background

Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis, but their precise role in ALF is unknown. Silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation influences multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation. In this study, we examined the link between ferroptosis and pyroptosis and the upstream regulatory mechanisms.

Research motivation

The most effective treatment for ALF at present is liver transplantation. However, liver transplants are not widely available because of the lack of donors and the high cost of medical care. Therefore, therapies for ALF are imminent.

Research objectives

To explore the link between ferroptosis and pyroptosis and the upstream regulatory mechanisms.

Research methods

Animal and cellular models of ALF were developed. The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were tested with automatic biochemistry instrument. Iron, reactive oxygen species, and glutathione levels were measured using commercial kits. SIRT1, p53, acetylated p53 (Ac-p53), glutathione peroxidase 4 (GPX4), gasdermin D (GSDMD), solute carrier family 7a member 11 (SLC7A11), and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein expression levels were measured through Western blot analysis.

Research results

AST and ALT levels were elevated in the serum of ALF patients. SIRT1, SLC7A11, and GPX4 expressions were decreased and Ac-p53, p53, GSDMD, and ACSL4 levels were elevated in human ALF liver tissue. In 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.

Research conclusions

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

Research perspectives

Our research is only limited to cellular and mouse models and has not been applied to clinical studies. Although we found decreased SIRT1 expression in human ALF liver tissue, whether SIRT1 activator is effective for acute liver injury and failure in patients is unknown, and further safety and efficacy studies are required.