MechAInistic: An LLM-guided Multi-Agent System for Reasoning over Genome-Scale Constraint-Based Metabolic Models

Constraint-based metabolic modeling is a powerful way to study the mechanistic basis of cellular states and disease, but its effective use demands substantial computational expertise and careful coordination of multi-step analyses. We developed MechAInistic to lower this barrier and enable researchers to ask complex biological questions in natural language. Harnessing large language models, MechAInistic is a multi-agent system organized around an Architect-Reviewer pattern that transforms a natural-language question into an executable, model-grounded workflow and generates a structured report. The system supports a variety of tasks, including pathway comparison, perturbation analysis, drug-target exploration, and literature-grounded interpretation across paired metabolic model states. We tested MechAInistic on two drug-repurposing use cases. For Naive B cells from Rheumatoid Arthritis (RA) paired with healthy controls, the system quantified the metabolic rewiring driving disease, prior