Reconstruction of human metabolic models with large language models.

Proceedings of the National Academy of Sciences of the United States of America
Authors
Keywords
Abstract

Genome-scale metabolic models (GEMs) have become essential tools for understanding human metabolism. Here, we introduce Human2, a consensus human GEM with enhanced precision and biological relevance, which leverages large language models (LLMs) and GitHub Action checks to streamline automated, efficient, and collaborative curation. Human2 supports the reconstruction of tissue- and organ-specific models tailored to sex- and age-specific human groups. By integrating transcriptomic, proteomic, and kinetic data, we reveal distinct metabolic features across these groups, such as significant differences in arachidonic acid and leukotriene metabolism. The specific models were integrated into a dynamic whole-body framework, marking an enzyme-constrained dynamic model that simulates interorgan metabolite exchanges under varying nutritional states, from feeding to fasting. Our work highlights the transformative role of LLMs in GEM reconstruction and introduces a whole-body dynamic simulation that integrates kinetic data, offering a powerful resource for multiscale human metabolism modeling.

Year of Publication
2026
Journal
Proceedings of the National Academy of Sciences of the United States of America
Volume
123
Issue
15
Pages
e2516511123
Date Published
04/2026
ISSN
1091-6490
DOI
10.1073/pnas.2516511123
PubMed ID
41950094
Links