Agentic AI uncovers conserved cross-tissue protein co-abundance programs inaccessible to single-dataset analysis

Researchers presented an LLM-agent framework for cross-tissue protein co-abundance analysis, applied to 820 pairwise combinations of 41 human tissues and fluids, identifying 1,833 conserved clusters across 406 tissue pairs, with colon, synovial fluid, blood, cerebrospinal fluid, and bone marrow as the most broadly connected tissues. The framework, detailed in an arXiv preprint (2608.28990v1), uncovered non-obvious relationships such as skin-bone marrow and colon-breast clusters, and generated mechanistic hypotheses including a brain-gut axis and a liver-bone marrow stress-response axis. Code and data are available on GitHub.

arXiv:2608.28990v1 Announce Type: new Abstract: Protein co-abundance clusters preserved across tissues can reveal shared disease mechanisms and candidate therapeutic targets, particularly when proteins implicated in organ-confined diseases converge in peripheral or accessible tissues. However, previous cross-tissue studies have focused on biologically pre-selected tissue pairs, leaving most possible combinations and non-obvious relationships unexplored. We present an LLM-agent framework for large-scale, evidence-grounded comparison of tissue-specific protein co-abundance networks. The framework constructs tissue networks, derives pairwise consensus clusters, and integrates evidence from expression atlases, protein interaction and complex databases, pathway annotations, disease catalogues, and literature. Applied to all 820 pairwise combinations of 41 human tissues and fluids, it identified 1,833 conserved co-abundance clusters across 406 tissue pairs. Colon, synovial fluid, blood, cerebrospinal fluid, and bone marrow were the most broadly connected tissues, while the most cluster-rich pairs were dominated by bone marrow. The analysis also highlighted non-obvious relationships: skin-bone marrow exceeded the anatomically adjacent bone-bone marrow pair, while colon-breast contained cancer-relevant clusters involving extracellular-matrix remodeling, lipid metabolism, and immune modulation. Cluster-level analyses generated further mechanistic hypotheses, including a brain-gut extracellular-vesicle/redox/serotonin-cofactor axis and a liver-bone marrow stress-response axis involving genes linked to white matter disease. These results provide a global, comparable landscape of conserved protein co-abundance and a hypothesis-generating resource for mechanistic and therapeutic exploration. Code and data are available at https://github.com/Gry1005/AgenticAI-conserved-cross-tissue-protein-co-abundance.