Zhao, Y.; Chen, Y.; Du, J.; Sun, Q.; Wang, R.; Chen, C.

Drug repositioning presents a compelling strategy to accelerate therapeutic development by uncovering new indications for existing compounds. However, current computational methods are often limited in their ability to integrate heterogeneous biomedical data and model the intricate, multi-scale relationships underlying drug-disease associations, while large-scale experimental validation remains prohibitively resource-intensive. Here we present DREAM-GNN (Dual-Route Embedding-Aware Model for Graph Neural Networks), a multi-view deep graph learning framework that incorporates biomedical domain knowledge with two complementary graphs capturing both topological structure and feature similarity to enable accurate and biologically meaningful prediction of drug-disease associations. Extensive experiments on benchmark datasets demonstrate that DREAM-GNN significantly outperforms current state-of-the-art methods in recovering artificially removed repositioning candidates. These results establish DREAM-GNN as a robust and generalizable computational framework with broad potential to streamline drug discovery and advance precision medicine.