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Identifying multiscale translational safety biomarkers using a network-based systems approach.

Giulia Callegaro1, Johannes P Schimming1, Janet Piñero González2

  • 1Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.

Iscience
|March 10, 2023
PubMed
Summary
This summary is machine-generated.

This study introduces a network-based approach to identify liver injury biomarkers from rat data, applicable for early human safety screening in vitro. Novel biomarkers TRIB3 and MTHFD2 aid in detecting drug-induced stress responses.

Keywords:
BioinformaticsGene networkTranscriptomics

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Area of Science:

  • Toxicology and Pharmacology
  • Systems Biology
  • Biomarker Discovery

Background:

  • Current animal testing for drug and chemical safety faces challenges in human translation due to species differences.
  • Human in vitro models offer improved species relevance but may lack in vivo complexity.
  • Bridging the gap between in vivo and in vitro models is crucial for accurate safety assessment.

Purpose of the Study:

  • To develop a network-based method for identifying in vivo liver injury biomarkers translatable to in vitro human safety screening.
  • To address multiscale translational problems in drug and chemical safety assessment.
  • To discover novel biomarkers for early detection of liver toxicity.

Main Methods:

  • Applied weighted gene correlation network analysis (WGCNA) to a large rat liver transcriptomic dataset.
  • Identified co-regulated gene clusters (modules) associated with liver pathologies.
  • Utilized BAC-eGFPHepG2 reporter systems for compound screening and validation.

Main Results:

  • Identified gene modules statistically linked to liver pathologies, including one enriched for ATF4-regulated genes associated with hepatocellular necrosis.
  • This ATF4-regulated module was found to be preserved in human liver in vitro models.
  • TRIB3 and MTHFD2 were identified as novel candidate stress biomarkers within the key module.

Conclusions:

  • The network-based approach successfully derived in vivo liver injury biomarkers applicable to in vitro human early safety screening.
  • TRIB3 and MTHFD2 serve as promising novel biomarkers for detecting stress responses.
  • The study demonstrates the utility of BAC-eGFPHepG2 reporters in identifying compounds with potential early safety signals via ATF4-dependent pathways.