{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T01:35:29Z","timestamp":1768354529069,"version":"3.49.0"},"reference-count":82,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T00:00:00Z","timestamp":1745280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100021952","name":"Office of Data Science Strategy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100021952","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Toxicol."],"abstract":"<jats:p>We developed the Reasoning Over Biomedical Objects linked in Knowledge Oriented Pathways (ROBOKOP) application as an open-source knowledge graph system to support evidence-based biomedical discovery and hypothesis generation. This study aimed to apply ROBOKOP to suggest biological mechanisms that might explain the hypothesized relationship between exposure to the herbicide and lipid-lowering drug clofibrate, an activator of peroxisome proliferator-activated receptor-\u03b1 (PPARA), and hepatic fibrosis. We queried ROBOKOP to first establish that it could demonstrate a relationship between clofibrate and PPARA as a validation test and second to identify intermediary genes and biological processes or activities that might relate the activation of PPARA by clofibrate to hepatic fibrosis. Queries of ROBOKOP returned several paths relating clofibrate, PPARA, and hepatic fibrosis. One path suggested the following: <jats:italic>clofibrate \u2013 affects \/ increases_ expression_ of \/ increases_ activity_ of \/ increases_ response_ to \/ decreases_ response_ to \/ is_ related_ to \u2013 PPARA \u2013 is_ actively_ involved_ in \u2013 cellular response to lipid \u2013 actively_ involves \u2013 CCL2 \u2013 is_ genetically_ associated_ with \u2013 hepatic fibrosis<\/jats:italic>. This result established a relationship between clofibrate and PPARA and further suggested that PPARA is actively involved in the cellular response to lipids, which actively involves the chemokine ligand CCL2, a gene genetically associated with hepatic fibrosis; thus, we can infer that PPARA, upon activation by clofibrate, plays a role in hepatic fibrosis. We conclude that ROBOKOP can be used to derive insights into biological mechanisms that might explain relationships between environmental exposures and liver toxicity.<\/jats:p>","DOI":"10.3389\/ftox.2025.1549268","type":"journal-article","created":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T05:25:42Z","timestamp":1745299542000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Elucidating the mechanistic relationships between peroxisome proliferator\u2013activated receptors and hepatic fibrosis using the ROBOKOP knowledge graph"],"prefix":"10.3389","volume":"7","author":[{"given":"Karamarie","family":"Fecho","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nyssa","family":"Tucker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon-Michael","family":"Beasley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott S.","family":"Auerbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Bizon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Tropsha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1002\/etc.34","article-title":"Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment","volume":"29","author":"Ankley","year":"2010","journal-title":"Enviro Toxic Chem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"D1276","DOI":"10.1093\/nar\/gkac1085","article-title":"DrugCentral 2023 extends human clinical data and integrates veterinary drugs","volume":"51","author":"Avram","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"B3","unstructured":"Text mining provider\n          \n          \n            \n              Baumgartner\n              B.\n            \n          \n          \n          2024"},{"key":"B4","doi-asserted-by":"publisher","first-page":"4968","DOI":"10.1021\/acs.jcim.9b00683","article-title":"ROBOKOP KG and KGB: integrated knowledge graphs from federated sources","volume":"59","author":"Bizon","year":"2019","journal-title":"J. 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