Unlocking liver physiology: comprehensive pathway maps for mechanistic understanding.

Area of Science:

• * Computational toxicology and systems biology.
• * Bioinformatics and pathway analysis.
• * Novel Approach Methodologies (NAMs).

Background:

• * Traditional animal testing for chemical safety is being replaced by advanced in silico methods.
• * Physiological Maps (PMs) offer a structured way to represent complex biological mechanisms.
• * Liver function is crucial for chemical metabolism and toxicity, necessitating detailed mechanistic understanding.

Purpose of the Study:

• * To introduce two novel, machine-readable Liver Physiological Maps (PMs) for key liver functions.
• * To provide interactive, curated graphical representations of liver lipid metabolism and bile acid pathways.
• * To support the development of human-relevant in vitro testing strategies for chemical safety assessment.

Main Methods:

• * Manual literature curation and integration of pathway resources and expert knowledge.
• * Validation of cell-type specificity using Human Protein Atlas datasets.
• * Cross-comparison with existing Adverse Outcome Pathway (AOP) networks to identify coverage and gaps.

Main Results:

• * Developed LiverLipidPM and LiverBilePM detailing specific metabolic and transport pathways.
• * Interactive maps allow visualization, external ontology linkage, and experimental data overlay.
• * Identified novel chemical targets and potential molecular initiating events for AOP extension.

Conclusions:

• * Liver PMs are valuable resources for hepatology, hepatotoxicity research, and AOP refinement.
• * These maps facilitate the development of computational models and mode-of-action ontologies.
• * PMs can be extended for systems biology, drug discovery, and in vitro test battery development.