Fig. 1. Study design.

A database containing 1497 human gene–expression data from both 1263 human samples and 234 mouse samples was mined to build a validated Boolean implication network-based computational model of disease continuum states in inflammatory bowel disease (IBD) [Supplementary Data 1 lists all the datasets, showcasing sample heterogeneity]. Paths, clusters and a list of genes in the network-based model are prioritized to discover clinically actionable drug targets. The search yield PRKAB1 as a barrier-protective therapeutic target. Two PRKAB1-specific agonists were successfully tried in mice. In phase ‘0’ trials, one of the PRKAB1-agonist PF-06409577 was successfully used in patient-derived organoid models. Furthermore, the network-based model accurately classified the FDA-approved vs. the failed targets.