CREB is a potential marker associated with drug-induced liver injury: Identification and validation through...

Area of Science:

• Pharmacology
• Toxicology
• Molecular Biology

Background:

• Drug-induced liver injury (DILI) is a significant hurdle in pharmaceutical development and post-market drug safety.
• Current toxicogenomic methods are effective for mechanistic studies but impractical for early-stage compound screening.

Purpose of the Study:

• To identify transcription factors (TFs) relevant to DILI from toxicogenomic data for reporter gene assay development.
• To evaluate the potential of identified TFs as predictive biomarkers for DILI risk.

Main Methods:

• Comprehensive analysis of toxicogenomics (TGx) data, including Gene Set Enrichment Analysis (GSEA) on the Open TG-GATEs dataset.
• Reporter gene assays in HepG2 cells using drugs with known idiosyncratic toxicity (IDT) risks and S9 mix.
• Investigated the role of the PKA/CREB signaling pathway in drug-induced stress responses.

Main Results:

• Gene Set Enrichment Analysis (GSEA) identified CREB, NRF2, ELK-1, and E2F as DILI-relevant transcription factors.
• CREB activity showed a strong correlation with idiosyncratic toxicity (IDT) risk, unlike NRF2.
• CREB activation by high-risk drugs was mitigated by PKA inhibitor pretreatment, suggesting PKA/CREB pathway involvement.

Conclusions:

• CREB demonstrates potential as a sensitive biomarker for predicting drug-induced liver injury (DILI).
• The PKA/CREB signaling pathway appears to be a key regulator of cellular response to DILI-inducing drugs.