UniD3: A Knowledge Graph-Enhanced RAG Framework for Drug-Disease Discovery and Reasoning

Systematic characterization of drug-disease relationships is essential for drug discovery and repurposing, yet is hindered by the heterogeneity and rapid growth of biomedical literature. Existing datasets rely on labor-intensive curation and are often incomplete, while LLM-only approaches suffer from hallucination and weak evidence grounding. We introduce UniD3, a unified framework that integrates Large Language Models with Knowledge Graph-enhanced Retrieval-Augmented Generation (KG-RAG) to extract, organize, and validate drug-disease knowledge across Drug-Disease Matching (DDM), Drug Effectiveness Assessment (DEA), and Drug-Target Analysis (DTA). UniD3 processes 157,849 PubMed articles with Llama 3.3-70B and constructs knowledge graphs via a dual-stage strategy combining paper-level extraction with KG-level consolidation centered on drug and disease entities. These graphs support KG-RAG-based generation of structured datasets, evaluated through external benchmarks, fuzzy matching with curated resources, and clinician review. UniD3 produces six knowledge graphs and large-scale datasets, including 28,915 DDM, 15,042 DEA, and over 4,000 DTA QA pairs. External validation shows strong performance (F1: 0.85-0.87 for DDM/DEA; 0.82 for DTA), with clinician review confirming high reliability (AUROC = 0.90). KG-RAG-augmented models outperform standalone LLMs, and the UniD3 chatbot enables interpretable, citation-supported exploration of drug-disease relationships. UniD3 provides a scalable, extensible framework for transforming unstructured biomedical literature into high-quality, structured drug-disease knowledge, supporting AI-driven discovery, repurposing, and precision medicine.