CAREPath: semantic context-aware reasoning paths with mechanism-augmented embeddings for drug repurposing

Biomedical knowledge graphs 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 Context-Aware REasoning Path (CAREPath), a knowledge graph (KG)-large language model framework inspired by depth-search and breadth-search reasoning to balance mechanistic specificity, scalability, and context recovery. The depth-search strategy 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 breadth-search strategy 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 area under the precision-recall curve (AUPRC) in the disease cold-start setting among 18 baselines, improving performance by up to 3.6%. Additional analyses show that semantic short-path encoding contributes most to performance, while mechanism-context augmentation improves robustness under sparse path signals and strengthens gene ontology functional agreement. Case studies and recently U.S. Food and Drug Administration (FDA)-approved indications further demonstrate its practical relevance, positioning CAREPath as a framework that supplies interpretable mechanistic rationales where constrained path is available, while remaining robust when it is not. Source code is available at https://github.com/hamppy-song/CAREPath.