CAREPath: Semantic Context-Aware Reasoning Paths with Mechanism-Augmented Embeddings for Drug Repurposing
Biomedical knowledge graphs (BKGs) that include drugs, genes, and diseases support drug repurposing by connecting drugs to diseases through gene-mediated multi-hop paths, thereby enabling mechanism-of-action reasoning. However, deeper traversal does not necessarily improve mechanistic reasoning: long paths grow combinatorially and frequently pass through hub genes, producing irrelevant gene regulatory signals, whereas overly constrained or sparse paths may miss broader biological context. We propose CAREPath, a KG-LLM framework inspired by depth-first search (DFS)-like and breadth-first search (BFS)-like reasoning to balance mechanistic specificity, scalability, and context recovery. The DFS-like module constrains traversal to short disease-gene-drug paths, converts each path into a structured prompt, and encodes it with a biomedical language model to generate semantic path embeddings. Complementarily, the BFS-like module constructs entity-level mechanism-context embeddings from one-hop gene neighborhoods and enriches them through similarity-guided augmentation using pharmacologically related drugs and gene-signature-similar diseases. Across five biomedical KGs, CAREPath achieves the best overall AUPRC among 18 baselines, improving performance by up to 3.8%. Additional analyses show that semantic short-path encoding contributes most to performance, while mechanism-context augmentation improves robustness under sparse evidence and strengthens Gene Ontology functional agreement. Case studies and recently FDAapproved indications further demonstrate its practical relevance, positioning CAREPath as an interpretable framework for scalable and mechanism-aware drug repurposing. Source code is available at https://github.com/hamppy-song/CAREPath.