Mitochondrial-Related Genes May Be an Important Factor in the Immune Microenvironment of Decompensated Cirrhosis and Acute-on-Chronic Liver Failure: New Findings Based on Double Disease Analysis
Authors: Qin Yingying , Hong Haoyuan , Luo Bin , Jiang Lei , Shang Jin , Zhong Deyuan , Ma Shuoshuo , Liang Yuxin , Su Yuhao , Zhu Yizhun , Huang Xiaolun 
Published: October 2023

Abstract
Background
Decompensated cirrhosis (DC) is the late stage of chronic liver damage and is an essential risk factor for acute-on-chronic liver failure (ACLF). The abnormal function of mitochondria and the changes in the immune microenvironment are important factors of DC and ACLF. We aim to explore the role and molecular mechanism of mitochondrial-related genes in liver cirrhosis and ACLF and describe the role of mitochondrial-related genes in the immune microenvironment.
Materials and methods
The mRNA expression microarray of ACLF and DC liver tissue was obtained from the Gene Expression Omnibus (GEO) database, and human protein-coding genes located on mitochondria were retrieved from the MitoCarta3.0 database. A total of 1,136 human mitochondrial-related genes and differentially expressed genes (DEGs) of ACLF and DC were integrated and analyzed. Mitochondrial-related overlapping differential genes (mitoDEGs) were obtained. The Connectivity Map (CMap) database was used to search for small-molecule compounds based on the expression of the mitoDEGs. The potential mechanism of DC-related ACLF was revealed through functional enrichment analysis. The hub mitochondrial genes were then screened by Lasso regression and random forest, and the diagnostic map of the nomogram was constructed to evaluate the possibility of hub mitoDEGs developing into ACLF in DC. Subsequently, the ROC and calibration curves were used to assess the diagnostic efficiency of the nomogram. Finally, the CIBERSORT algorithm was performed to explore the details and link of the infiltrated immune cells in DC and ACLF.
Results
The study first obtained 2,437 and 2,612 identified DEGs in DC and ACLF, respectively, of which 1,563 were shared DEGs in the two diseases. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that these shared DEGs were mainly concentrated in focal adhesion, ECM–receptor interaction, tight junction, pathogenic Escherichia coli infection, leukocyte transendothelial migration, the phagosome, and other pathways. Among them, there are 117 mitochondrial-related DEGs. The CMap database predicts the potential of small molecular therapies for DC and ACLF, including conivaptan and lacidipine. Machine learning algorithms, such as Lasso regression analysis and random forest, finally identified three hub mitoDEGs, COQ10A, HSD17B8, and AKR1B10, potentially acting on closely DC-related ACLF. The results of immune cell infiltration revealed the relationship between these genes in the immune microenvironment of DC and ACLF.
Conclusion
We identified the diagnostic map of ACLF based on COQ10A, HSD17B8, and AKR1B10, revealed that these three hub mitoDEGs may be important factors in the immune microenvironment of DC and ACLF, and predicted the potential drugs that interfere with the development of DC into ACLF.