دورية أكاديمية
أعرض في EDS

The involvement of the Stat1/Nrf2 pathway in exacerbating Crizotinib-induced liver injury: implications for ferroptosis.

التفاصيل البيبلوغرافية
العنوان: The involvement of the Stat1/Nrf2 pathway in exacerbating Crizotinib-induced liver injury: implications for ferroptosis.
المؤلفون: Guo L; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.; Institute of Clinical Pharmacy, Central South University, Changsha, China.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China., Ma J; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.; Institute of Clinical Pharmacy, Central South University, Changsha, China.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China., Xiao M; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.; Institute of Clinical Pharmacy, Central South University, Changsha, China.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China., Liu J; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.; Institute of Clinical Pharmacy, Central South University, Changsha, China.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China., Hu Z; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.; Institute of Clinical Pharmacy, Central South University, Changsha, China.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China., Xia S; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.; Institute of Clinical Pharmacy, Central South University, Changsha, China.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China., Li N; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China., Yang Y; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.; Institute of Clinical Pharmacy, Central South University, Changsha, China.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China.; Department of Pharmacy, Wuzhou Gongren Hospital, Wuzhou, China., Gong H; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.; Institute of Clinical Pharmacy, Central South University, Changsha, China.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China., Xi Y; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.; Institute of Clinical Pharmacy, Central South University, Changsha, China.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China., Fu R; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.; Institute of Clinical Pharmacy, Central South University, Changsha, China.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China., Jiang P; Department of Pharmacy, Jining No 1 People's Hospital, Jining Medical University, Jining, China., Xia C; Chia Tai Tianqing Pharmaceutical Group Co. Ltd, Lianyungang, Jiangsu, China., Lauschke VM; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.; Institute of Clinical Pharmacy, Central South University, Changsha, China.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China.; Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77, Stockholm, Sweden., Yan M; Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China. yanmiao@csu.edu.cn.; Institute of Clinical Pharmacy, Central South University, Changsha, China. yanmiao@csu.edu.cn.; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China. yanmiao@csu.edu.cn.
المصدر: Cell death & disease [Cell Death Dis] 2024 Aug 19; Vol. 15 (8), pp. 600. Date of Electronic Publication: 2024 Aug 19.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Pub. Group
مواضيع طبية MeSH: Ferroptosis*/drug effects , NF-E2-Related Factor 2*/metabolism , Crizotinib*/pharmacology , Crizotinib*/adverse effects , Chemical and Drug Induced Liver Injury*/metabolism , Chemical and Drug Induced Liver Injury*/pathology , Chemical and Drug Induced Liver Injury*/genetics , STAT1 Transcription Factor*/metabolism , STAT1 Transcription Factor*/genetics, Humans ; Animals ; Mice ; Signal Transduction/drug effects ; Male ; Phenylenediamines/pharmacology ; Mice, Inbred C57BL ; Hepatocytes/metabolism ; Hepatocytes/drug effects ; Phosphorylation/drug effects
مستخلص: Crizotinib carries an FDA hepatotoxicity warning, yet analysis of the FAERS database suggests that the severity of its hepatotoxicity risks, including progression to hepatitis and liver failure, might be underreported. However, the underlying mechanism remains poorly understood, and effective intervention strategies are lacking. Here, mRNA-sequencing analysis, along with KEGG and GO analyses, revealed that DEGs linked to Crizotinib-induced hepatotoxicity predominantly associate with the ferroptosis pathway which was identified as the principal mechanism behind Crizotinib-induced hepatocyte death. Furthermore, we found that ferroptosis inhibitors, namely Ferrostatin-1 and Deferoxamine mesylate, significantly reduced Crizotinib-induced hepatotoxicity and ferroptosis in both in vivo and in vitro settings. We have also discovered that overexpression of AAV8-mediated Nrf2 could mitigate Crizotinib-induced hepatotoxicity and ferroptosis in vivo by restoring the imbalance in glutathione metabolism, iron homeostasis, and lipid peroxidation. Additionally, both Stat1 deficiency and the Stat1 inhibitor NSC118218 were found to reduce Crizotinib-induced ferroptosis. Mechanistically, Crizotinib induces the phosphorylation of Stat1 at Ser727 but not Tyr701, promoting the transcriptional inhibition of Nrf2 expression after its entry into the nucleus to promote ferroptosis. Meanwhile, we found that MgIG and GA protected against hepatotoxicity to counteract ferroptosis without affecting or compromising the anti-cancer activity of Crizotinib, with a mechanism potentially related to the Stat1/Nrf2 pathway. Overall, our findings identify that the phosphorylation activation of Stat1 Ser727, rather than Tyr701, promotes ferroptosis through transcriptional inhibition of Nrf2, and highlight MgIG and GA as potential therapeutic approaches to enhance the safety of Crizotinib-based cancer therapy.
(© 2024. The Author(s).)
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معلومات مُعتمدة: Grant No. 82274033 National Natural Science Foundation of China (National Science Foundation of China)
المشرفين على المادة: 0 (NF-E2-Related Factor 2)
53AH36668S (Crizotinib)
0 (STAT1 Transcription Factor)
0 (Phenylenediamines)
0 (STAT1 protein, human)
تواريخ الأحداث: Date Created: 20240819 Date Completed: 20240819 Latest Revision: 20240822
رمز التحديث: 20240822
مُعرف محوري في PubMed: PMC11333746
DOI: 10.1038/s41419-024-06993-z
PMID: 39160159
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-4889
DOI:10.1038/s41419-024-06993-z