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Current paradigms for developing synergistic therapies, however, remain chronically inefficient and resource\u2010intensive due to the prohibitive scale of the combinatorial screening space and a lack of computational frameworks for navigating signaling crosstalk. This work introduces a hybrid in silico and in vitro lead discovery platform that integrates knowledge\u2010augmented large language models (LLMs) with an oxygen\u2010supplemented 3D spheroid system. By comparing compound mechanism\u2010of\u2010action annotations with disease\u2010relevant signaling crosstalk, the LLM framework nominates drug pairs with predictive performance and interpretable, pathway\u2010based rationales. This computational pipeline is complemented by an engineered 3D spheroid model that utilizes oxygen supplementation to mitigate artifactual necrosis, a common confounder that masks synergistic signals in standard screening. Using this approach to screen 3,592 natural products, we identified berberine\u2010enzalutamide as an in vitro combination hit that re\u2010sensitized resistant prostate cancer cells to AR blockade. Molecular and transcriptomic profiling revealed changes in mTORC1 and AMPK signaling that were consistent with the pathway\u2010based hypothesis generated by LLM. These results establish proof of concept that mechanism\u2010informed language modeling coupled with 3D screening can prioritize and experimentally evaluate drug\u2010combination hypotheses at an early stage of discovery.<\/jats:p>","DOI":"10.1002\/advs.78186","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:45:45Z","timestamp":1791517545000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanism\u2010Informed Language Modeling and Oxygenated 3D Screening Identify Berberine\u2013Enzalutamide Synergy in Prostate Cancer Models"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3759-5330","authenticated-orcid":false,"given":"Chih\u2010Hui","family":"Lo","sequence":"first","affiliation":[{"name":"Bioengineering Department University of California Los Angeles Los Angeles California USA"},{"name":"College of Pharmacy National Defense Medical University 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