{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T01:05:38Z","timestamp":1784077538180,"version":"3.55.0"},"reference-count":55,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"FONDECYT Regular","doi-asserted-by":"publisher","award":["1231911"],"award-info":[{"award-number":["1231911"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FONDEF IDEA","award":["ID24I10362"],"award-info":[{"award-number":["ID24I10362"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>The progression of prostate cancer to castration-resistant disease (CRPC) remains a clinical challenge in which oxidative stress intersects with the PI3K\/AKT\u2013androgen receptor (AR) axis. Quercetin (QRC) is a redox-active dietary flavonol, yet its mechanistic impact on CRPC is incompletely defined. Here, we tested whether QRC suppresses AR output by directly modulating AKT. C4-2B and 22Rv1 CRPC cell lines were treated with increasing QRC concentrations, with or without enzalutamide (Enz). Proliferation and viability were monitored by IncuCyte imaging and SYTOX Green incorporation. AKT phosphorylation (S473), AR phosphorylation (S210\/213), AR abundance and localization, and prostate-specific antigen (PSA) secretion were assessed by immunoblotting, immunofluorescence, and dot blot, respectively. Docking and molecular dynamic simulations were performed to identify and evaluate a putative QRC-binding site on AKT. QRC produced a dose-dependent cytostatic effect (IC50 24.37 \u03bcM in C4-2B; 21.54 \u03bcM in 22Rv1) without marked cell death, reduced pAKT(S473) by up to 80%, decreased pAR(S210\/213), and diminished nuclear AR and PSA secretion. Simulations suggested a putative druggable allosteric pocket in the AKT1 N-lobe, with G159 emerging as a potential anchor residue. Enz cotreatment with QRC did not produce additive effects, consistent with a model in which QRC acts upstream of ligand-driven AR activation and thereby limits the incremental benefit of AR antagonism under these conditions. These data support QRC as an AKT\u2013AR axis modulator in CRPC and provide a target engagement framework beyond simple ROS scavenging.<\/jats:p>","DOI":"10.3390\/antiox15030393","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T09:44:41Z","timestamp":1773999881000},"page":"393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Quercetin Inhibits AKT Ser473 Phosphorylation and Disrupts AKT\u2013Androgen Receptor Signaling in Castration-Resistant Prostate Cancer Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"F\u00e9lix","family":"Duprat","sequence":"first","affiliation":[{"name":"Laboratorio de Lipoprote\u00ednas y C\u00e1ncer, Departamento de Fisiopatolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1890-4616","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Az\u00f3car-Plaza","sequence":"additional","affiliation":[{"name":"Laboratorio de Lipoprote\u00ednas y C\u00e1ncer, Departamento de Fisiopatolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5254-782X","authenticated-orcid":false,"given":"Mar\u00eda Paz","family":"Castillo-C\u00e1ceres","sequence":"additional","affiliation":[{"name":"Laboratorio de Lipoprote\u00ednas y C\u00e1ncer, Departamento de Fisiopatolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7411-599X","authenticated-orcid":false,"given":"Yerko","family":"Rivas","sequence":"additional","affiliation":[{"name":"Laboratorio de Lipoprote\u00ednas y C\u00e1ncer, Departamento de Fisiopatolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javiera","family":"Sanzana-Rosas","sequence":"additional","affiliation":[{"name":"Laboratorio de Lipoprote\u00ednas y C\u00e1ncer, Departamento de Fisiopatolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Pampaloni","sequence":"additional","affiliation":[{"name":"Laboratorio de Lipoprote\u00ednas y C\u00e1ncer, Departamento de Fisiopatolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4782-5145","authenticated-orcid":false,"given":"Gabriel","family":"Olivas-Henr\u00edquez","sequence":"additional","affiliation":[{"name":"Laboratorio de Lipoprote\u00ednas y C\u00e1ncer, Departamento de Fisiopatolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9879-7710","authenticated-orcid":false,"given":"Jorge","family":"Toledo","sequence":"additional","affiliation":[{"name":"Laboratorio de Lipoprote\u00ednas y C\u00e1ncer, Departamento de Fisiopatolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2678-3627","authenticated-orcid":false,"given":"Jhon L\u00f3pez","family":"Villa","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8320000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Bertinat","sequence":"additional","affiliation":[{"name":"Laboratorio de Lipoprote\u00ednas y C\u00e1ncer, Departamento de Fisiopatolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nery","family":"Jara","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Vallejos-Almirall","sequence":"additional","affiliation":[{"name":"Departamento de Ciencia y Tecnolog\u00eda de los Alimentos, Facultad de Farmacia, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6577-9970","authenticated-orcid":false,"given":"Alexis","family":"Salas","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0544-4463","authenticated-orcid":false,"given":"Iv\u00e1n","family":"Gonz\u00e1lez-Chavarr\u00eda","sequence":"additional","affiliation":[{"name":"Laboratorio de Lipoprote\u00ednas y C\u00e1ncer, Departamento de Fisiopatolog\u00eda, Facultad de 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