{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:29:42Z","timestamp":1785432582032,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,13]]},"group-title":"Systems Biology","reference-count":72,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["R35GM119770"],"award-info":[{"award-number":["R35GM119770"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Grand Challenges Catalyst Award"],"award-info":[{"award-number":["Grand Challenges Catalyst Award"]}],"id":[{"id":"https:\/\/ror.org\/043mer456","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,22]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>LLM agents are increasingly used for scientific reasoning, but their fluent-sounding outputs can diverge from verifiable computational evidence, limiting their reliability for biomedical hypothesis generation. We developed MechAInistic, a multi-agent system in which an independently configured Reviewer agent supervises a planning Architect agent at each stage of the workflow, with all reasoning grounded in executable mechanistic-model analyses rather than language-model text alone. The Reviewer scores plans and intermediate results against pre-specified rubrics and triggers re-planning or re-execution when scores fall below threshold, producing an auditable chain from a natural-language question to model-derived evidence and cited literature. We instantiate the system over paired constraint-based metabolic models using COBRApy, supporting pathway comparison, perturbation analysis, drug-target exploration, and literature interpretation across healthy and disease states. We evaluated MechAInistic on two immune-cell therapeutic hypothesis-generation tasks. For rheumatoid arthritis versus healthy naive B-cell models, it identified mitochondrial metabolic rewiring and nominated Devimistat\/CPI-613 as an investigational OGDH-centered hypothesis. For multiple sclerosis CD4+ Th17 versus healthy models, it identified NADP-dependent isocitrate dehydrogenase as a candidate target and proposed ivosidenib, with vorasidenib as a mechanistically complementary alternative. Comparator analyses against general-purpose LLM systems showed that plausible biological narratives can lack auditable model grounding, whereas MechAInistic preserves the computational reasoning path from prompt to result.<\/jats:p>\n                <jats:sec>\n                  <jats:title>GRAPHICAL ABSTRACT<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"723319v4_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.11.723319","type":"posted-content","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T02:45:15Z","timestamp":1778726715000},"source":"Crossref","is-referenced-by-count":0,"title":["MechAInistic: A Reviewer-Supervised Multi-Agent LLM System for Auditable Mechanistic Drug-Hypothesis Generation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6388-2958","authenticated-orcid":false,"given":"Josh","family":"Loecker","sequence":"first","affiliation":[{"name":"Biochemistry Department, University of Nebraska-Lincoln, Lincoln, NE, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narayna","family":"Pujara","sequence":"additional","affiliation":[{"name":"Biochemistry Department, University of Nebraska-Lincoln, Lincoln, NE, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Bryant","sequence":"additional","affiliation":[{"name":"Biochemistry Department, University of Nebraska-Lincoln, Lincoln, NE, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7528-3568","authenticated-orcid":false,"given":"Bhanwar Lal","family":"Puniya","sequence":"additional","affiliation":[{"name":"Biochemistry Department, University of Nebraska-Lincoln, Lincoln, NE, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2404-5561","authenticated-orcid":false,"given":"Prakash","family":"Packrisamy","sequence":"additional","affiliation":[{"name":"Biochemistry Department, University of Nebraska-Lincoln, Lincoln, NE, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4411-8433","authenticated-orcid":false,"given":"Ahmed Abdeen","family":"Hamed","sequence":"additional","affiliation":[{"name":"Biochemistry Department, University of Nebraska-Lincoln, Lincoln, NE, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3653-1906","authenticated-orcid":false,"given":"Tom\u00e1\u0161","family":"Helikar","sequence":"additional","affiliation":[{"name":"Biochemistry Department, University of Nebraska-Lincoln, Lincoln, NE, US"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072413350783000_2026.05.11.723319v4.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-026-10644-y"},{"key":"2026072413350783000_2026.05.11.723319v4.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-026-10652-y"},{"key":"2026072413350783000_2026.05.11.723319v4.3","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1038\/s43588-025-00849-y","article-title":"SciToolAgent: a knowledge-graph-driven scientific agent for multitool integration","volume":"5","year":"2025","journal-title":"Nat. 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