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However, the liver injury induced by crizotinib is a clinical problem that needs to be solved urgently. Therefore, the mechanism underlying crizotinib-induced liver injury must be elucidated to identify prevention and treatment methods. By establishing the mouse and cell models of crizotinib-induced liver injury, we found that crizotinib induced apoptosis in mouse liver tissue, L02 cells, and HepG2 cells. After treatment with crizotinib, the N6-methyladenosine (m6A) reading protein YTHDF3 was aberrantly downregulated in mouse liver tissue and L02 cells. RNA sequencing, m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq), and MeRIP-qPCR were performed to identify the target gene of Lcn2. The upregulation of LCN2 was detected in both in vitro and in vivo models. Genetic inhibition of Lcn2 resulted in a reduction in the incidence of liver cell apoptosis induced by crizotinib. Additionally, knocking down YTHDF3 increased the mRNA stability and expression level of LCN2, whereas the overexpression of YTHDF3 inhibited the expression of LCN2 and apoptosis induced by crizotinib in L02 cells. Further mechanistic studies revealed a potential association between the YTHDF3 protein and Lcn2 mRNA and that YTHDF3 may affect the stability of Lcn2 mRNA in an m6A-dependent manner. Our findings revealed that the m6A reading protein YTHDF3-LCN2-apoptosis axis plays a critical role in mediating the hepatotoxicity of crizotinib, which provides potential intervention approaches for alleviating crizotinib-induced liver injury.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf154","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T18:42:27Z","timestamp":1762195347000},"source":"Crossref","is-referenced-by-count":0,"title":["N6-methyladenosine reader YTHDF3-mediated\n                    <i>Lcn2<\/i>\n                    mRNA stability promotes the hepatotoxicity of crizotinib"],"prefix":"10.1093","volume":"209","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7653-4696","authenticated-orcid":false,"given":"Ruijuan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052,","place":["China"]},{"name":"Henan Key Laboratory of Precision Clinical 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450052,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3328-5802","authenticated-orcid":false,"given":"Ke","family":"An","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052,","place":["China"]},{"name":"Henan Key Laboratory of Precision Clinical Pharmacy , Zhengzhou 450052,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8357-0898","authenticated-orcid":false,"given":"Jingyao","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052,","place":["China"]},{"name":"Henan Key Laboratory of Precision Clinical Pharmacy , Zhengzhou 450052,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052,","place":["China"]},{"name":"Henan Key Laboratory of Precision Clinical Pharmacy , Zhengzhou 450052,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052,","place":["China"]},{"name":"Henan Key Laboratory of Precision Clinical Pharmacy , Zhengzhou 450052,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0408-6721","authenticated-orcid":false,"given":"Yueqin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052,","place":["China"]},{"name":"Henan Key Laboratory of Precision Clinical Pharmacy , Zhengzhou 450052,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0392-6362","authenticated-orcid":false,"given":"Xin","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052,","place":["China"]},{"name":"Henan Key Laboratory of Precision Clinical Pharmacy , Zhengzhou 450052,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"2026021910562724300_kfaf154-B1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/5584_2022_721","article-title":"Epitranscriptomics changes the play: m6A RNA modifications in 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