Large Language Models Meet Biomedical Knowledge Graphs for Mechanistically Grounded Therapeutic Prioritization

Computer Science > Artificial Intelligence [Submitted on 17 Apr 2026] Large Language Models Meet Biomedical Knowledge Graphs for Mechanistically Grounded Therapeutic Prioritization Chih-Hsuan Wei, Chi-Ping Day, Zhizheng Wang, Christine C. Alewine, Betty Tyler, Hasan Slika, David Saraf, Chin-Hsien Tai, Joey Chan, Robert Leaman, Zhiyong Lu Drug repurposing is often framed as a candidate identification task, but existing approaches provide limited guidance for distinguishing biologically plausible candidates from historically well-connected ones. Here we introduce DrugKLM, a hybrid framework that integrates biomedical knowledge graph structure with large language model-based mechanistic reasoning to enable mechanistically grounded therapeutic prioritization. Across benchmark datasets, DrugKLM outperforms knowledge graph-only and language model-only baselines, including TxGNN. Beyond improved recall, DrugKLM confidence scores exhibit functional alignment with molecular phenotypes: higher scores are associated with transcriptional signatures linked to improved survival across 12 TCGA cancers. The scoring framework preferentially captures biologically perturbational signals rather than historical indication patterns. Expert curation across five cancers further reveals systematic differences in prioritization behavior, with DrugKLM elevating candidates supported by coherent mechanistic rationale and disease-specific clinical context. Together, these results establish DrugKLM as an evidence-integrative framework that translates heterogeneous biomedical data into mechanistically interpretable and clinically grounded therapeutic hypotheses. Comments: 24 pages, 5 figures in main text Subjects: Artificial Intelligence (cs.AI) Cite as: arXiv:2604.19815 [cs.AI]   (or arXiv:2604.19815v1 [cs.AI] for this version)   https://doi.org/10.48550/arXiv.2604.19815 Focus to learn more Submission history From: Chih-Hsuan Wei [view email] [v1] Fri, 17 Apr 2026 15:29:52 UTC (1,315 KB) Access Paper: view license Current browse context: cs.AI < prev   |   next > new | recent | 2026-04 Change to browse by: cs References & Citations NASA ADS Google Scholar Semantic Scholar Export BibTeX Citation Bookmark Bibliographic Tools Bibliographic and Citation Tools Bibliographic Explorer Toggle Bibliographic Explorer (What is the Explorer?) Connected Papers Toggle Connected Papers (What is Connected Papers?) Litmaps Toggle Litmaps (What is Litmaps?) scite.ai Toggle scite Smart Citations (What are Smart Citations?) Code, Data, Media Demos Related Papers About arXivLabs Which authors of this paper are endorsers? | Disable MathJax (What is MathJax?)