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However, whether the TCA cycle is involved in cholestatic liver injury (CLI) induced by DEHP and the protective effect of dimethyl fumarate (DMF), which is used to supplement TCA intermediate metabolites, remained unclear. Here, mice were randomized into five groups (<jats:italic>n<\/jats:italic>\u2009=\u20096\/group): (1) Control, (2) DEHP (200\u2009mg\/kg\/day), (3) DMF (100\u2009mg\/kg\/day), (4) DEHP\u2009+\u2009DMF (30\u2009mg\/kg\/day) and (5) DEHP\u2009+\u2009DMF (100\u2009mg\/kg\/day). Our data demonstrated that DEHP exposure upregulated total bile acid (TBA) levels and broke the TCA cycle, resulting in reduced fumaric acid and malic acid. However, we further supplemented fumaric acid with DMF and found that DMF effectively reversed the high levels of TBA, alkaline phosphatase (ALP) and glutamyl transpeptidase (GGT) induced by DEHP in mice. Meanwhile, pathological results in the liver showed that DMF improved bile duct cell damage, inflammatory cell infiltration, collagen deposition and necrosis caused by DEHP. In addition, we found that DEHP elevated the level of interleukin (IL)\u20101\u03b2, IL\u20106, TNF\u2010\u03b1 and MDA and decreased the level of SOD in the mouse liver, which was effectively reversed by DMF treatment. Besides, DMF upregulated the expression of Nrf2 and NQO1 in the liver of DEHP\u2010exposed mice. For in\u00a0vitro validation, AML\u201012 cells were treated with (1) Control, (2) DEHP (250\u2009\u03bcM), (3) DEHP\u2009+\u2009DMF (10\u2009\u03bcM), (4) DEHP\u2009+\u2009DMF (25\u2009\u03bcM) and (5) DEHP\u2009+\u2009DMF (50\u2009\u03bcM). DEHP exposure increased the expression of IL\u20101\u03b2, IL\u20106 and TNF\u2010\u03b1, which was mitigated by DMF, while ML385, an Nrf2 inhibitor, could counteract the anti\u2010inflammatory effects of DMF. These findings indicate that DEHP broke the TCA cycle of the mouse liver, and DMF supplementation protects against DEHP\u2010induced CLI by activating the Nrf2\/NQO1 pathway.<\/jats:p>","DOI":"10.1111\/bcpt.70047","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T04:40:08Z","timestamp":1747284008000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["TCA Cycle Intermediate Mitigates Di(2\u2010ethylhexyl) Phthalate\u2010Induced Cholestatic Liver Injury Through Modulation of the Nrf2\/NQO1 Signalling Axis"],"prefix":"10.1111","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1134-5602","authenticated-orcid":false,"given":"Yue","family":"Jiang","sequence":"first","affiliation":[{"name":"School of Pharmacy Anhui Medical University  Hefei 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