Work

SCOPE-based target and pathway enrichment identifies the histamine H1 receptor as a regulator of exodosis

Year: 2026

Type: article

Abstract: Introduction: Phenotypic screening enables discovery of small molecules without requiring predefined targets, but mechanistic interpretation remains challenging due to polypharmacology and pathway complexity. Methods: We developed SCOPE (Screening Compound Ontology for Pathway Enrichment), a KNIME-based computational framework that links compound-level screening data to annotated targets and pathways to facilitate generation of mechanistic hypotheses. SCOPE integrates multi-source target annotations and performs sequential target- and pathway-level statistical enrichment using the screened compound library as the background to prioritize shared mechanisms of action. Results: Applied to a previously established high-throughput screen for modulators of endoplasmic reticulum (ER)-stress induced secretion of ER resident proteins, a process known as exodosis, SCOPE identified calcium signaling as the most enriched KEGG pathway without prior biological context. Its target enrichment revealed several G protein-coupled receptors (GPCRs) linked to inositol 1,4,5-trisphosphate receptors (IP3Rs)-mediated calcium signaling, with widespread antagonism of these receptors among compounds that reduced exodosis, implicating this pathway in the regulation of exodosis. Notably, SCOPE uncovered a novel role for the histamine receptor HRH1 in exodosis, which was validated by RNAi knockdown, gene knockout, and pharmacological modulation, implicating HRH1 as a potential therapeutic target for modulating exodosis. Discussion: These results highlight SCOPE's potential to prioritize experimentally testable targets and pathways from phenotypic screening data.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1972662