Lignature: A Comprehensive Database of Ligand Signatures to Predict Cell-Cell Communication

ABSTRACTLigand-receptor interactions mediate intercellular communication, inducing transcriptional changes that regulate physiological and pathological processes. Ligand-induced transcriptomic signatures can be used to predict active ligands; however, the absence of a comprehensive set of ligand-response signatures has limited their practical application in predicting ligand-receptor interactions. To bridge this gap, we developed Lignature, a curated database encompassing intracellular transcriptomic signatures for 362 human ligands, significantly expanding the repertoire of ligands with available intracellular response signatures. Lignature compiles signatures from published transcriptomic datasets and established resources such as CytoSig and ImmuneDictionary, generating both gene- and pathway-based signatures for each ligand. We applied Lignature to predict active ligands driving transcriptomic changes in controlledin vitroexperiments and real-world single-cell sequencing datasets. Lignature outperformed existing methods such as NicheNet, achieving higher accuracy in identifying active ligands at both the gene and pathway levels. These results establish Lignature as a robust platform for ligand signaling inference, providing a powerful tool to explore ligand-receptor interactions across diverse experimental and physiological contexts.