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However, methotrexate\u2010induced nephrotoxicity is a severe adverse reaction, of which the mechanisms remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An untargeted metabolomics analysis of serum from childhood acute lymphoblastic leukemia patients with delayed methotrexate excretion, with or without acute kidney injury, was performed to identify altered metabolites and metabolic pathways. An independent external validation cohort and in vitro HK\u20102 cell assays further verified the candidate metabolites, and explored the mechanisms underlying the nephrotoxicity of methotrexate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four metabolites showed significant differences between normal excretion and delayed excretion, seven metabolites reflected the differences between groups with or without acute kidney injury, and six pathways were finally enriched. In particular, oxidized glutathione was confirmed as a candidate metabolite involved in the toxicity of methotrexate. We further explored the role of glutathione deprivation\u2010induced ferroptosis on methotrexate cytotoxicity, and it was found that methotrexate overload significantly reduced cell viability, triggered reactive oxygen species and intracellular Fe<jats:sup>2+<\/jats:sup> accumulation, and altered the expression of ferroptosis\u2010related proteins in HK\u20102 cells. These methotrexate\u2010induced changes were alleviated or reversed by the administration of a ferroptosis inhibitor, further suggesting that ferroptosis promoted methotrexate\u2010induced cytotoxicity in HK\u20102 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings revealed complex metabolomic profiles and provided novel insights into the mechanism by which ferroptosis contributes to the nephrotoxic effects of methotrexate.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.30578","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T14:05:03Z","timestamp":1689343503000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Metabolomic profiling reveals the mechanisms underlying the nephrotoxicity of methotrexate in children with acute lymphoblastic 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