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Updated: Nov 2, 2025
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
Insight into molecular mechanisms underlying hepatic dysfunction in severe COVID-19 patients using systems biology
Sarah Musa Hammoudeh1, Arabella Musa Hammoudeh2, Poorna Manasa Bhamidimarri1
1Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates.
Insights
Severe coronavirus disease 2019 (COVID-19) patients show liver transcriptional changes, including tissue remodeling and suppressed detoxification, leading to liver dysfunction. These findings highlight molecular mechanisms behind COVID-19-associated liver injury.
Area of Science:
- Hepatology
- Virology
- Molecular Biology
Background:
- Coronavirus disease 2019 (COVID-19) is a global pandemic with over 105 million cases and 2.3 million deaths.
- Liver dysfunction and elevated liver enzymes are common extrapulmonary manifestations in COVID-19 patients, affecting approximately 53%.
Purpose of the Study:
- To investigate transcriptional alterations in the liver tissue of severe COVID-19 patients.
- To understand the molecular basis of COVID-19-associated liver dysfunction.
Main Methods:
- RNA sequencing (RNA-seq) analysis of liver autopsy samples from severe COVID-19 patients and non-COVID donors.
- Identification and functional enrichment analysis of differentially expressed genes.
- Comparison of COVID-19 liver gene signatures with those of various liver diseases (cirrhosis, fibrosis, NAFLD, hepatitis A/B/C).
- Quantitative reverse transcription PCR (qRT-PCR) validation of selected gene expression in blood samples.
Main Results:
- Significant upregulation of transcripts involved in tissue remodeling (e.g., G-protein coupled receptors, DNAJB1, IGF2, EGFR, HDGF) in severe COVID-19 liver tissue.
- Substantial overlap between COVID-19 liver transcriptome and disease signatures of liver cirrhosis, fibrosis, NAFLD, and hepatitis.
- Significant suppression of metabolic and mitochondrial function transcripts (e.g., cytochrome P450 family, ACAD11, CIDEB, GNMT, GPAM), indicating reduced hepatic detoxification capacity.
- Validation of upregulated DNAJB1, HSP90AB1 and downregulated CYP39A1 in blood plasma of COVID-19 patients with liver dysfunction.
Conclusions:
- Severe COVID-19 induces significant transcriptional shifts in the liver.
- These shifts involve tissue remodeling, mitochondrial dysfunction, and impaired hepatic detoxification.
- These molecular changes likely contribute to the clinically observed liver dysfunction in severe COVID-19 patients.
Background:
The coronavirus disease 2019 (COVID-19), a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide, was described to be frequently accompanied by extrapulmonary manifestations, including liver dysfunction. Liver dysfunction and elevated liver enzymes were observed in about 53% of COVID-19 patients.
Aim:
To gain insight into transcriptional abnormalities in liver tissue of severe COVID-19 patients that may result in liver dysfunction.
Methods:
The transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed. Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways. The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis, fibrosis, non-alcoholic fatty liver disease (NAFLD), and hepatitis A/B/C. Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR.
Results:
Analysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including G-coupled protein receptors family genes, DNAJB1, IGF2, EGFR, and HDGF. Concordantly, the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling (liver cirrhosis, Fibrosis, NAFLD, and hepatitis A/B/C). Moreover, we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function, including cytochrome P450 family members, ACAD11, CIDEB, GNMT, and GPAM. Consequently, drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity. In correspondence with the RNA-seq data analysis, we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction.
Conclusion:
Severe COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling, mitochondrial dysfunction and lower hepatic detoxification resulting in the clinically observed liver dysfunction.
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