DeepRoot: A KG-Coordinated Multi-Agent System for Therapeutic Reasoning over Historical Medical Texts

Extracting multi-step explanations from knowledge graphs poses a combinatorial challenge requiring both heuristic guidance (as candidates proliferate with depth) and credit assignment (as path quality emerges over extended sequences). Frontier LLMs, strong on knowledge/reasoning benchmarks, offer a compelling source of such heuristics, yet their knowledge comes sans guarantees and compositional performance degrades as chains lengthen. We thus present TESSERA, a 3-part neuro-symbolic framework that uses LLMs in a circumscribed role: for local discriminative judgement rather than autonomous multi-step generation; the knowledge graph then defines the hypothesis space enforcing hard structural constraints, and MCTS coordinates the long-horizon search with principled credit assignment via backpropagation. LLMs perform dual roles as a prior policy biasing exploration and a comparative state evaluator supplying reward signals. Evaluation on drug mechanism elucidation across two complementary knowledge graphs demonstrates fidelity to curated biology while surfacing coherent alternative mechanisms, with ablations confirming discriminative contribution from both LLM components. Beyond its current application, our framework offers a general paradigm for compositional reasoning over structured knowledge.

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.

Treatment reasoning underpins every therapeutic decision, integrating disease context, comorbidities, medications, contraindications, and evolving biomedical knowledge to select an appropriate therapy. It is inherently iterative: candidates are weighed against many constraints, revised as evidence emerges, and grounded in verifiable sources. Here we introduce ATHENA-R1, an AI agent for treatment reasoning across all FDA approved drugs since 1939, trained by reinforcement learning over a universe of 212 biomedical tools. At each step it identifies missing information, selects and runs relevant tools, and incorporates the evidence. To train it without human-annotated traces, we build a two-level self-learning framework: multi-agent systems construct the tools, tasks, and reasoning trajectories for supervised fine-tuning, then reinforcement learning with scientific feedback rewards reasoning quality (evidence gathering, grounded tool use, logical non-redundancy). Across five benchmarks of 3,168 drug reasoning tasks and 456 patient treatment cases, ATHENA-R1 outperforms language models and tool-use systems, reaching 94.7% accuracy on open-ended drug reasoning and 82.9% on treatment reasoning, 17.8 and 10.7 points above GPT-5. In blinded evaluations by experts from 28 rare disease organizations, it is preferred over reference models on all criteria, and physicians rated it favorably on complex hospitalized cardiovascular and infectious-disease cases. Adverse-event hypotheses it generated, tested in electronic health records from 5.4 million patients, reached adjusted odds ratios of 1.48-1.84, with no elevation among negative controls. Because it requires knowing what evidence to seek before concluding, treatment reasoning has long been hard for AI; we show it can be reframed as a learnable process of iterative evidence gathering that reinforcement learning can train AI to perform.