JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

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Roles of PANoptosis and related genes in acute liver failure: neoteric insight from bioinformatics analysis and animal experiment verification

Author(s): Tiantian GE, Yao CHEN, Lantian PANG, Junwei SHAO, Zhi CHEN
Affiliation(s): State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; more
Corresponding email(s): zjuchenzhi@zju.edu.cn, sjw507@163.com
Key Words: Acute liver failure; PANoptosis; Gene Expression Omnibus (GEO); Biomarker; Therapeutic target

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Tiantian GE, Yao CHEN, Lantian PANG, Junwei SHAO, Zhi CHEN. Roles of PANoptosis and related genes in acute liver failure: neoteric insight from bioinformatics analysis and animal experiment verification[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2300678

@article{title="Roles of PANoptosis and related genes in acute liver failure: neoteric insight from bioinformatics analysis and animal experiment verification",
author="Tiantian GE, Yao CHEN, Lantian PANG, Junwei SHAO, Zhi CHEN",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2300678"
}

%0 Journal Article
%T Roles of PANoptosis and related genes in acute liver failure: neoteric insight from bioinformatics analysis and animal experiment verification
%A Tiantian GE
%A Yao CHEN
%A Lantian PANG
%A Junwei SHAO
%A Zhi CHEN
%J Journal of Zhejiang University SCIENCE B
%P 353-370
%@ 1673-1581
%D in press
%I Zhejiang University Press & Springer
doi="https://doi.org/10.1631/jzus.B2300678"

TY - JOUR
T1 - Roles of PANoptosis and related genes in acute liver failure: neoteric insight from bioinformatics analysis and animal experiment verification
A1 - Tiantian GE
A1 - Yao CHEN
A1 - Lantian PANG
A1 - Junwei SHAO
A1 - Zhi CHEN
J0 - Journal of Zhejiang University Science B
SP - 353
EP - 370
%@ 1673-1581
Y1 - in press
PB - Zhejiang University Press & Springer
ER -
doi="https://doi.org/10.1631/jzus.B2300678"

Abstract
Chinese Summary
Academic Network
Reviewer Comment

Abstract: BackgroundPANoptosis has the features of pyroptosis, apoptosis, and necroptosis. Numerous studies have confirmed the diverse roles of various types of cell death in acute liver failure (ALF), but limited attention has been given to the crosstalk among them. In this study, we aimed to explore the role of PANoptosis in ALF and uncover new targets for its prevention or treatment.
MethodsThree ALF-related datasets (GSE14668, GSE62029, and GSE74000) were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). Hub genes were identified through intersecting DEGs, genes obtained from weighted gene co-expression network analysis (WGCNA), and genes related to PANoptosis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein‍‒‍protein interaction (PPI) analyses and gene set enrichment analysis (GSEA) were performed to determine functional roles. Verification was performed using an ALF mouse model.
ResultsOur results showed that expression of seven hub genes (B-cell lymphoma-2-modifying factor (BMF), B-cell lymphoma-2-interacting protein 3-like (BNIP3L), Caspase-1 (CASP1), receptor-interacting protein kinase 3 (RIPK3), uveal autoantigen with coiled-coil domains and ankyrin repeats protein (UACA), uncoordinated-5 homolog B receptor (UNC5B), and Z-DNA-binding protein 1 (ZBP1)) was up-regulated in liver samples of patients. However, in the ALF mouse model, the expression of BNIP3L, RIPK3, phosphorylated RIPK3 (P-RIPK3), UACA, and cleaved caspase-1 was up-regulated, while the expression of CASP1 and UNC5B was down-regulated. The expression of ZBP1 and BMF increased only during the development of ALF, and there was no significant change in the end stage. Immunofluorescence of mouse liver tissue showed that macrophages expressed all seven markers. Western blot results showed that pyroptosis, apoptosis, and necroptosis were always involved in lipopolysaccharide (LPS)/d-galactosamine (d-gal)‍-induced ALF mice. The ALF cell model showed that bone marrow-derived macrophages (BMDMs) form PANoptosomes after LPS stimulation.
ConclusionsOur results suggest that PANoptosis of macrophages promotes the development of ALF. The seven new ALF biomarkers identified and validated in this study may contribute to further investigation of diagnostic markers or novel therapeutic targets of ALF.

泛凋亡（PANoptosis）及其相关基因在急性肝衰竭中的作用：通过生物信息学分析和动物实验验证所获得的新见解

葛田田¹，陈瑶¹，庞澜天²，邵骏威³，陈智¹
¹浙江大学医学院附属第一医院传染病诊治国家重点实验室，国家感染性疾病临床医学研究中心，国家传染病医学中心，感染性疾病诊治协同创新中心，中国杭州市， 310003
²浙江大学医学院附属第二医院感染科，中国杭州市， 310009
³浙江大学医学院附属第二医院肝胆胰外科，中国杭州市， 310009
摘要：泛凋亡具有焦亡、凋亡和坏死性凋亡的特征。尽管大量研究已证实各类型细胞的死亡在急性肝衰竭（ALF）中发挥着不同作用，但对它们间的互作关注较少。本研究旨在探讨泛凋亡在ALF中的作用，并挖掘可作为预防或治疗ALF的新靶点。本研究首先从基因表达综合数据库（GEO）中下载三个与ALF相关的数据集（GSE14668、GSE62029和GSE74000），从中筛选差异表达基因（DEGs），并通过加权基因共表达网络分析（WGCNA）对上述基因和泛凋亡相关基因集取交集得到枢纽基因；通过基因本体论（GO）、京都基因与基因组百科全书（KEGG）、蛋白质-蛋白质互作（PPI）和基因集富集分析（GSEA）确定枢纽基因功能；最后利用ALF小鼠和细胞模型进行验证。结果表明，在ALF患者肝脏样本中，7个枢纽基因（BMF、BNIP3L、CASP1、RIPK3、UACA、UNC5B、ZBP1）表达水平均上调；在ALF小鼠模型中，BNIP3L、RIPK3、P-RIPK3、UACA和cleaved caspase-1表达上调，而CASP1和UNC5B的表达下调；ZBP-1和BMF的表达仅在造模过程中升高，终末期则无明显变化。小鼠肝组织免疫荧光显示，这7个枢纽基因在巨噬细胞中均有表达；western blot结果表明，在脂多糖（LPS）/d-氨基半乳糖（d-gal）引起的ALF小鼠模型中，焦亡、凋亡和坏死性凋亡均有发生；ALF细胞模型实验显示，骨髓源巨噬细胞在LPS刺激后形成泛凋亡小体。综上，巨噬细胞的泛凋亡有可能加速ALF的进展，此外本研究鉴定并验证的7个ALF枢纽基因将有希望作为未来深入研究ALF的诊断标志物或新的治疗靶点。

关键词组：急性肝衰竭；泛凋亡；基因表达综合数据库；生物标志物；治疗靶点

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泛凋亡（PANoptosis）及其相关基因在急性肝衰竭中的作用：通过生物信息学分析和动物实验验证所获得的新见解

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