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The nuclear factor erythroid 2\u2013related factor 2 (NRF2) pathway, a master regulator of antioxidant and detoxification responses, plays a critical role in mitigating cellular toxicity and maintaining lipid homeostasis. A multidisciplinary approach was applied to uncover the molecular toxicology of NRF2 in lipid metabolism. Transcriptomic meta\u2010analysis of GEO datasets identified differentially expressed NRF2\u2010regulated genes in lipid\u2010associated chronic liver diseases (CLD). Clinical meta\u2010analysis synthesized evidence on NRF2 activators and their effects on lipid\u2010related toxic endpoints. Network pharmacology was used to map overlapping targets between NRF2 activation and lipid toxicity, while molecular docking assessed the binding potential of NRF2 activators with KEAP1, a negative regulator of NRF2. Transcriptomic analysis revealed widespread dysregulation of NRF2\u2010dependent antioxidant genes such as GPX4, HMOX1, and NQO2, with 3178 DEGs significantly associated with oxidative stress, ferroptosis, and glutathione metabolism. Clinical meta\u2010analysis demonstrated that NRF2 activators reduced toxic lipid parameters, including triglycerides (\u2193\u200921.81%), LDL (\u2193\u200918.36%), and total cholesterol (\u2193\u200914.15%). Network pharmacology identified 985 overlapping genes linking NRF2 activation to oxidative stress, lipid peroxidation, and fatty acid metabolism. Sixteen natural and synthetic NRF2 activators were highlighted, with molecular docking showing strong KEAP1 binding by quercetin (\u20139.2\u2009kcal\/mol) and luteolin (\u20139.2\u2009kcal\/mol), consistent with disruption of KEAP1\u2013NRF2 interactions and detoxification pathway activation. This integrative molecular toxicology study establishes NRF2 as a central regulator at the interface of oxidative stress and lipid metabolism. Both natural and synthetic NRF2 activators mitigate toxic lipid accumulation and oxidative injury, supporting NRF2 modulation as a promising strategy for preventing and treating lipid metabolic disorders such as NAFLD, atherosclerosis, and metabolic syndrome.<\/jats:p>","DOI":"10.1002\/jbt.70633","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T09:02:17Z","timestamp":1765184537000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["NRF2 Pathway Activation as a Molecular Toxicology Mechanism in Oxidative Stress and Lipid Metabolic Disorders"],"prefix":"10.1002","volume":"39","author":[{"given":"Muhammad","family":"Arif Asghar","sequence":"first","affiliation":[{"name":"College of Pharmacy Chongqing Medical University Chongqing PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lie","family":"Yuan","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chongqing Medical University Chongqing PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chongqing Medical University Chongqing PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixin","family":"Tang","sequence":"additional","affiliation":[{"name":"College of Public Health Chongqing Medical University Chongqing PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Wan","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chongqing Medical University Chongqing PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Chu","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chongqing Medical University Chongqing PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasir","family":"Bashir","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Biotechnology Government College University Faisalabad Faisalabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0107-0532","authenticated-orcid":false,"given":"Li Ping","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Social and Preventive Medicine, Center for Population Health (CePH), Faculty of Medicine Universiti Malaya Kuala Lumpur Malaysia"},{"name":"Department of Epidemiology and Health Statistics, School of Public Health Fujian Medical University Fujian Fuzhou China"},{"name":"Department of Medicine, College of Medicine Korea University Seoul Seongbuk\u2010gu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chongqing Medical University Chongqing PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6297-9969","authenticated-orcid":false,"given":"Qinjian","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chongqing Medical University Chongqing PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-020-01204-y"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25073694"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2023.188890"},{"issue":"494","key":"e_1_2_12_5_1","article-title":"Valproic Acid\u2010Induced Oxidative Stress: Systematic Review, Meta\u2010Analysis and Network Pharmacology Highlights Disruption in Antioxidant Pathways in Rodents","author":"Asghar M. 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