{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:03:18Z","timestamp":1790053398216,"version":"4.0.1"},"reference-count":52,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173560"],"award-info":[{"award-number":["82173560"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82020108027"],"award-info":[{"award-number":["82020108027"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82173560"],"award-info":[{"award-number":["82173560"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82020108027"],"award-info":[{"award-number":["82020108027"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005047","name":"Natural Science Foundation of Liaoning Province","doi-asserted-by":"publisher","award":["2026-MS-231"],"award-info":[{"award-number":["2026-MS-231"]}],"id":[{"id":"10.13039\/501100005047","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005047","name":"Natural Science Foundation of Liaoning Province","doi-asserted-by":"publisher","award":["2023JH2\/20200159"],"award-info":[{"award-number":["2023JH2\/20200159"]}],"id":[{"id":"10.13039\/501100005047","id-type":"DOI","asserted-by":"publisher"}]},{"name":"High-level Talents Support Foundation of China Medical University","award":["2400022054"],"award-info":[{"award-number":["2400022054"]}]},{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention (China Medical University), Ministry of Education"},{"name":"China Medical University","award":["CXTD2022004"],"award-info":[{"award-number":["CXTD2022004"]}]},{"award":["CXTD2022004"],"award-info":[{"award-number":["CXTD2022004"]}],"id":[{"id":"https:\/\/ror.org\/00v408z34","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Hypercholesterolemia and hyperlipidemia are major contributors to the pathogenesis and progression of atherosclerosis and cardiovascular diseases (CVDs). Nuclear factor erythroid-derived 2-like 2 (NRF2) exerts antioxidant and anti-inflammatory effects while regulating glucose and lipid metabolism. However, the precise role and molecular mechanisms of NRF2 in hepatic cholesterol metabolism remain incompletely understood. Approach and Results: ApoE-knockout (ApoE-KO) mice were crossed with hepatocyte-specific Nrf2-knockout (Nrf2(H)-KO) mice to explore how NRF2 modulated cholesterol metabolism and the progression of atherosclerosis in vivo. Atherosclerotic lesion areas in Nrf2(H)-KO;ApoE-KO mice were significantly reduced compared with control counterparts (Nrf2-LoxP;ApoE-KO). Total cholesterol and LDL-cholesterol levels in plasma of Nrf2(H)-KO;ApoE-KO mice were significantly decreased, consistent with atherosclerotic phenotypes. Furthermore, hepatic triglyceride levels and cholesterol contents were increased in Nrf2(H)-KO;ApoE-KO mice. The hepatic transcriptomic analysis highlighted lipid metabolism pathway alterations in Nrf2(H)-KO;ApoE-KO mice, and carboxylesterase 1 (Ces1s) and lipocalin gene family member major urinary proteins (Mups) clusters markedly reduced expression in Nrf2(H)-KO;ApoE-KO livers. Liver proteomics analysis corroborated the transcriptomic findings. The current findings suggest that NRF2-modulated CES1s and MUPs may regulate cholesterol metabolism in the ApoE-KO model. Conclusions: Hepatocyte-specific Nrf2 deficiency significantly reduced plasma cholesterol levels, thereby attenuating atherosclerotic plaque formation and progression in the ApoE-KO background. This study established NRF2 in hepatocytes as a potential therapeutic target for controlling hypercholesterolemia and preventing atherosclerosis development.<\/jats:p>","DOI":"10.3390\/antiox15091183","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:03:47Z","timestamp":1789977827000},"page":"1183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatocyte-Specific Nrf2 Deficiency Alters Cholesterol Metabolism, Leading to Mitigated Atherosclerosis in ApoE-Knockout Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Junying","family":"Jiao","sequence":"first","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, China Medical University, Ministry of Education, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China"},{"name":"Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China"},{"name":"School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Ning","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Zhixuan","family":"Hong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic 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