Simple SummaryMolecules mediating long-distance inter-tissue communication from source to target tissues is essential to coordinate physiological functions and maintain health. A well-known example is insulin, which originates from the pancreas and targets multiple tissues, such as the liver and muscle, in order to control glucose metabolism and to keep the blood glucose level stable. However, knowledge about inter-tissue communication molecules is not always well-organized as in the cited insulin case, and there is currently no specialized database to extensively collect known inter-tissue communication molecules and their communication routes from source tissues to target tissues. In this paper, through a manual literature curation of nearly 190,000 publications, we established a database called IntiCom-DB, which contains 1408 inter-tissue communication relationships supported by experimental evidence. In IntiCom-DB, users can conveniently browse or search for inter-tissue communication molecules and their source tissues, target tissues, functions, and other related information. This database will enhance our understanding of human health and disease biology, and it will facilitate the development of treatments for complex diseases.AbstractInter-tissue communication (ITC) is critical for maintaining the physiological functions of multiple tissues and is closely related to the onset and development of various complex diseases. Nevertheless, there is no well-organized data resource for known ITC molecules with explicit ITC routes from source tissues to target tissues. To address this issue, in this work, we manually reviewed nearly 190,000 publications and identified 1408 experimentally supported ITC entries in which the ITC molecules, their communication routes, and their functional annotations were included. To facilitate our work, these curated ITC entries were incorporated into a user-friendly database named IntiCom-DB. This database also enables visualization of the expression abundances of ITC proteins and their interaction partners. Finally, bioinformatics analyses on these data revealed common biological characteristics of the ITC molecules. For example, tissue specificity scores of ITC molecules at the protein level are often higher than those at the mRNA level in the target tissues. Moreover, the ITC molecules and their interaction partners are more abundant in both the source tissues and the target tissues. IntiCom-DB is freely available as an online database. As the first comprehensive database of ITC molecules with explicit ITC routes to the best of our knowledge, we hope that IntiCom-DB will benefit future ITC-related studies.