Abstract
The Reactome Pathway Knowledgebase (www.reactome.org) provides expert-curated information on human biological pathways, molecular interactions, and disease mechanisms. However, its complex data model and keyword-based search interface present accessibility barriers for non-expert users. In contrast, general-purpose conversational AI systems offer intuitive natural language interfaces but lack the domain-specificity, transparent sourcing, and factual reliability required for scientific applications. To address this gap, we developed React-to-Me (https://reactome.org/chat), a domain-specific conversational assistant that enables users to query Reactome using natural language while maintaining scientific rigor and source traceability. React-to-Me integrates hybrid retrieval-augmented generation (RAG) with constrained language model generation to ensure that all responses are grounded in curated Reactome content and directly linked to corresponding knowledgebase entries. When internal coverage is insufficient, the system defers to trusted external biomedical sources rather than generating speculative or unverified content. Computational benchmarking confirmed that combining semantic vector search with lexical keyword-based matching substantially improved contextual grounding and factual precision relative to dense-only retrieval baselines. In blinded expert evaluations, grounded responses were more likely to receive higher quality ratings than ungrounded counterparts (OR = 2.01, 95% CI: 1.50-2.69, p < 0.01), with significant gains in factual accuracy (OR = 2.97), biological specificity (OR = 2.88), and mechanistic depth (OR = 1.83). User surveys further indicated strong satisfaction with ease of use (92%), citation reliability (88%), and factual accuracy (85%), with accuracy emerging as the strongest predictor of overall confidence (ρ (rho) = 0.81). These findings demonstrate that domain-specific grounding can markedly improve the reliability and usability of conversational AI for biological knowledge exploration. React-to-Me provides a transparent and scientifically robust interface for accessing and exploring Reactome content and is freely available at https://reactome.org/chat.