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This study investigated the effects of these sex hormones\u2014testosterone and \u03b2\u2010estradiol\u2014on Nrf2 expression and its relation to key factors in metastasis, apoptosis, and drug resistance in HepG2 HCC cell line. HepG2 cells were exposed to testosterone or \u03b2\u2010estradiol at viability\u2010equivalent doses. Oxidative stress was quantified by total oxidant status (TOS), malondialdehyde (MDA), and total antioxidant capacity (TAC) assays. Apoptosis was evaluated by Annexin V\/PI flow cytometry. mRNA levels of Nrf2, MRP\u20101 (multidrug resistance protein 1), MMP\u20109 (matrix metalloproteinase\u20109), BCL2, and SIRT1 were assessed via qRT\u2010PCR. At viability\u2010equivalent doses, \u03b2\u2010estradiol elicited dose\u2010dependent apoptosis in HepG2 cells (total: 47.4% at V\u2085\u2080 vs. 32.7% for testosterone;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), predominantly late\u2010stage (34.5% vs. 21.8%;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001). Concomitantly, \u03b2\u2010estradiol decreased TOS (maximal at V\u2084\u2080,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) and MDA (all doses,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) while increasing TAC (medium\/high doses,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05)\u2014effects not observed with testosterone (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&gt;\u20090.05). \u03b2\u2010estradiol induced downregulation of Nrf2, BCL2, MMP\u20109, and MRP\u20101 mRNA (moderate\/high doses;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05 vs. control). Conversely, testosterone upregulated SIRT1 across doses (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05), unaffected by \u03b2\u2010estradiol (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&gt;\u20090.05). \u03b2\u2010Estradiol mitigates oxidative stress, induces apoptosis, and suppresses pro\u2010survival, metastatic, and chemoresistant pathways\u2014contrasting testosterone's minimal effects. These findings align with HCC's male predominance and highlight the hormone\u2010modulated strategies' potential for future therapeutic exploration.\n                  <\/jats:p>","DOI":"10.1002\/jbt.70730","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T08:53:49Z","timestamp":1770886429000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sex Hormone\u2010Dependent Modulation of Nrf2 and Its Association With Apoptosis, Metastasis, and Drug Resistance in Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"40","author":[{"given":"Ala","family":"Alban","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Iran University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fereshteh","family":"Barjesteh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Iran University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1819-853X","authenticated-orcid":false,"given":"Yaser","family":"Mohammadi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Iran University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4258-9047","authenticated-orcid":false,"given":"Afsaneh","family":"Dashtaki","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Iran University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6823-8638","authenticated-orcid":false,"given":"Elham","family":"Bahreini","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Iran University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.acr.2020.10.001"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31288"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology12070984"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-12-93"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13092085"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2015.3025"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2024.104361"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101510"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0015-0"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology11020300"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2015.11.022"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-024-03191-8"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00705"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.etap.2009.03.005"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-023-02767-0"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4402233"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2022.120443"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21134777"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2024.110043"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox9070617"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10565-020-09517-5"},{"key":"e_1_2_13_23_1","unstructured":"M. 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