{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:08:22Z","timestamp":1789189702471,"version":"build-2803163510"},"reference-count":70,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Universities and Research","award":["2022P5LPHS"],"award-info":[{"award-number":["2022P5LPHS"]}]},{"award":["2022P5LPHS"],"award-info":[{"award-number":["2022P5LPHS"]}],"id":[{"id":"https:\/\/ror.org\/0341vw408","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007195","name":"University of Naples \u201cFederico II\u201d","doi-asserted-by":"crossref","award":["FRA 2022"],"award-info":[{"award-number":["FRA 2022"]}],"id":[{"id":"10.13039\/100007195","id-type":"DOI","asserted-by":"crossref"}]},{"award":["FRA 2022"],"award-info":[{"award-number":["FRA 2022"]}],"id":[{"id":"https:\/\/ror.org\/05290cv24","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic disorder characterized by dysregulated lipid handling and bile acid signaling, processes controlled by PPARs and FXR. We report that RT206, a 2-aryloxy-3-phenyl-propanoic acid derivative, combines partial PPAR\u03b1\/\u03b3 agonism with positive allosteric modulation of FXR. Transactivation assays and endogenous gene-expression profiling confirmed activation of PPAR\u03b1\/\u03b3-responsive genes. RT206 showed no intrinsic FXR agonism, yet it robustly potentiated FXR-dependent gene transcription in HepG2 cells in the presence of structurally distinct orthosteric agonists. Grating-coupled interferometry revealed weak interaction with apo-FXR that was enhanced by orthosteric ligands, consistent with cooperative ternary complex formation. Docking and molecular dynamics supported a model in which RT206 engages the non-orthosteric FXR S2 site, while orthosteric agonists occupy the S1 primary pocket. Comparison with guggulsterone revealed distinct predicted S2 interaction patterns associated with divergent transcriptional outcomes in vitro. In fatty acid-loaded HepG2 cells, RT206 combined with FXR agonists modulated FXR- and PPAR-regulated metabolic genes and modestly reduced neutral-lipid accumulation. These findings identify RT206 as a proof-of-principle scaffold that integrates partial PPAR\u03b1\/\u03b3 agonism with ligand-dependent potentiation of FXR activity and support its further evaluation in more advanced liver models.<\/jats:p>","DOI":"10.3390\/biom16091316","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:38:39Z","timestamp":1789040319000},"page":"1316","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RT206 Couples Partial PPAR\u03b1\/\u03b3 Agonism with Ligand-Dependent Allosteric Potentiation of FXR Signaling in Liver Cells"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6880-2681","authenticated-orcid":false,"given":"Manuela","family":"Leo","sequence":"first","affiliation":[{"name":"Department of Sciences and Technologies, University of Sannio, 82100 Benevento, 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