LLM-Guided Monte Carlo Tree Search over Knowledge Graphs: Composing Mechanistic Explanations for Drug-Disease Pairs

Historical medical archives and traditional medicines hold immense potential for drug discovery and remain a primary source for current drug development. However, pre-ontological prose and idiosyncratic taxonomies prevent the standardization and medical modernization of the data for use in current biomedical pipelines. Furthermore, no existing LLM agent system, whether tool-calling, retrieval-augmented, or agentic deep-research, can convert such text into verifiable drug-discovery leads at scale. We close this gap with DeepRoot, a multi-agent LLM system that jointly builds and utilizes a verified knowledge graph, showing that grounding and reasoning -- often conflated -- are separable axes the system can compose for therapeutic reasoning. Applied to the Shen Nong Ben Cao Jing, DeepRoot recovers $10$ of $21$ held-out compound-disease treatment pairs at R@$20$ ($47.6\%$ vs $4.8\%$ for a raw corpus LLM and $\sim\!2.4\%$ random) and dominates an LLM-as-judge audit for reasoning quality over baseline LLMs and LLMs with direct tool-call access to the same APIs DeepRoot itself queries. Tool-using LLMs hallucinate evidence on $87\%$ of claims, versus 7-10% for DeepRoot. Graph-only inference hallucinates $0\%$ but ranks lowest on reasoning coherence; DeepRoot KG+LLM is the only condition to win on both axes, pointing toward a route for systematic mining and repurposing of historical medical knowledge.

Large language models (LLMs) can generate biomedical hypotheses, but it remains unclear whether they truly reason from scientific evidence or simply produce convincing-sounding ideas. To study this, we combine three major biological databases: the Kyoto Encyclopedia of Genes and Genomes (KEGG), Rhea, and UniProt, into a unified biochemical knowledge graph and construct a benchmark of 550 paths connecting enzyme sources to rare disease endpoints, yielding 13,200 hypotheses from six LLMs under four conditions varying the biological information each model receives: source enzyme only, full biological path, or source and disease endpoint only. Hypotheses are scored using an expert-derived five-criterion rubric on a 1-5 scale per criterion. We find that models given both the source and disease endpoint often produce the highest-scoring hypotheses, showing that LLMs can generate compelling ideas from minimal information. However, these hypotheses are less grounded in the evidence. In contrast, models given the full biological path generate hypotheses more consistent with known mechanistic relationships. We call this evidence-disciplined reasoning. To confirm this effect, we shuffled intermediate path steps while keeping endpoints fixed. Evidence grounding dropped significantly (delta = -0.793, p < 0.001), confirming models genuinely used path structure during reasoning. Our findings show that knowledge graphs support hypothesis generation in two ways: they identify biological endpoint pairs absent from the literature, and their mechanistic paths guide how LLMs reason between them.

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 UniD$^3$, 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). UniD$^3$ 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. UniD$^3$ 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 UniD$^3$ chatbot enables interpretable, citation-supported exploration of drug-disease relationships. UniD$^3$ 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.