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However, the structure-activity relationships (SARs) and underlying mechanisms of their hepatic lipotoxicity remain unclear. This study systematically evaluated the effects of nine 4-AP isomers with linear (4-n-APs) and branched (4-t-APs) para-alkyl substituents on hepatic lipid metabolism in HepG2 cells. The results showed that all 4-n-APs significantly promoted intracellular triglyceride (TG) accumulation in a dose-dependent manner, whereas 4-t-APs exerted no such effects. The lipogenic potency of 4-n-APs followed an inverted U-shaped curve with increasing linear alkyl chain length. Either ER antagonism or ROS inhibition effectively mitigated 4-n-AP-induced hepatic lipogenesis, demonstrating the coordinated actions of ER signaling and oxidative stress underlying the lipotoxic phenotype. Collectively, linear 4-n-APs induce hepatic lipid accumulation through the combined contributions of ER agonism and excessive ROS production, while branched 4-t-APs lack such activity due to structural differences. These findings clarify the SAR framework for hepatic lipogenesis triggered by 4-AP congeners and the underlying dual ER-ROS mechanism, providing a scientific basis for assessing their environmental health risks.<\/jats:p>","DOI":"10.1021\/acs.est.6c06496","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T07:02:11Z","timestamp":1788764531000},"page":"26145-26157","source":"Crossref","is-referenced-by-count":0,"title":["Structure-Related\nActivity of 4-Alkylphenols\nin Hepatic Lipogenesis Regulated by Estrogen Receptor Agonism and\nOxidative Stress"],"prefix":"10.1021","volume":"60","author":[{"given":"Huinan","family":"Liu","sequence":"first","affiliation":[{"name":"Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Beijing, China, 101408"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2134-6652","authenticated-orcid":true,"given":"Zhendong","family":"Sun","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , , ,","place":["Hangzhou, China, 310024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiefeng","family":"Liang","sequence":"additional","affiliation":[{"name":"Shandong University , , ,","place":["Qingdao, China, 266237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqi","family":"Yan","sequence":"additional","affiliation":[{"name":"Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Beijing, China, 101408"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bobing","family":"Lu","sequence":"additional","affiliation":[{"name":"Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Hangzhou, China, 310024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5381-146X","authenticated-orcid":true,"given":"Xiaoxi","family":"Yang","sequence":"additional","affiliation":[{"name":"Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Su","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4759-5016","authenticated-orcid":true,"given":"Qian S.","family":"Liu","sequence":"additional","affiliation":[{"name":"Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2521-100X","authenticated-orcid":true,"given":"Qunfang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Beijing, China, 101408"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Hangzhou, China, 310024"]},{"name":"Jianghan University , , ,","place":["Wuhan, China, 430056"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6335-3917","authenticated-orcid":true,"given":"Guibin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Beijing, China, 101408"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"issue":"11","key":"2026092210103527500_cit1","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1111\/liv.15404","article-title":"Management of NAFLD\nin primary care\nsettings","volume":"42","author":"Wong","year":"2022","journal-title":"Liver Int."},{"issue":"2","key":"2026092210103527500_cit2","doi-asserted-by":"publisher","first-page":"243","DOI":"10.3390\/gidisord5020020","article-title":"Molecular\nmechanisms and mediators of hepatotoxicity resulting from an excess\nof lipids and non-alcoholic fatty liver disease","volume":"5","author":"Finelli","year":"2023","journal-title":"Gastrointest. 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