دورية أكاديمية
The involvement of the Stat1/Nrf2 pathway in exacerbating Crizotinib-induced liver injury: implications for ferroptosis.
العنوان: | The involvement of the Stat1/Nrf2 pathway in exacerbating Crizotinib-induced liver injury: implications for ferroptosis. |
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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).) |
References: | Front Oncol. 2022 Jan 28;12:749954. (PMID: 35155225) J Cell Mol Med. 2022 Aug;26(16):4492-4505. (PMID: 35855570) Med Res Rev. 2019 Nov;39(6):2105-2152. (PMID: 31111528) ACS Appl Mater Interfaces. 2022 Sep 28;14(38):42887-42903. (PMID: 36094079) J Immunol. 2007 Mar 15;178(6):3777-85. (PMID: 17339476) Cell Res. 2021 Feb;31(2):107-125. (PMID: 33268902) Drug Discov Today. 2016 Apr;21(4):648-53. (PMID: 26948801) Lung Cancer. 2016 Mar;93:17-9. (PMID: 26898609) Redox Biol. 2023 Sep;65:102825. (PMID: 37531930) Blood. 2003 Jul 1;102(1):254-61. (PMID: 12637327) Nat Rev Drug Discov. 2019 Apr;18(4):295-317. (PMID: 30610225) Hepatology. 2003 Jan;37(1):118-28. (PMID: 12500196) Cell Biol Toxicol. 2022 Jun;38(3):505-530. (PMID: 34401974) Br J Pharmacol. 2022 Aug;179(15):3991-4009. (PMID: 35303762) Free Radic Biol Med. 2022 Feb 20;180:95-107. (PMID: 35045311) Trends Cell Biol. 2024 Feb;34(2):150-160. (PMID: 37419738) J Hepatol. 2019 Jan;70(1):151-171. (PMID: 30266282) Cell Death Differ. 2022 Mar;29(3):467-480. (PMID: 35075250) Front Cell Dev Biol. 2022 Feb 02;9:809952. (PMID: 35186957) Trends Cell Biol. 2020 Jun;30(6):478-490. (PMID: 32413317) J Agric Food Chem. 2014 Jan 22;62(3):542-53. (PMID: 24377378) Cell Metab. 2020 Dec 1;32(6):920-937. (PMID: 33217331) J Ethnopharmacol. 2021 Dec 5;281:114489. (PMID: 34363931) ESMO Open. 2017 Aug 17;2(3):e000219. (PMID: 29209525) Signal Transduct Target Ther. 2023 Aug 14;8(1):301. (PMID: 37574511) Acta Pharmacol Sin. 2019 Jul;40(7):879-894. (PMID: 30568253) Cancer Res. 2004 Nov 15;64(22):8357-64. (PMID: 15548705) Nat Biotechnol. 2016 Jul 12;34(7):697-700. (PMID: 27404875) Immunity. 2003 Dec;19(6):793-802. (PMID: 14670297) J Cancer Res Clin Oncol. 2021 Mar;147(3):725-737. (PMID: 33387041) Mol Cell. 2023 Nov 2;83(21):3931-3939.e5. (PMID: 37863053) Expert Opin Ther Pat. 2018 May;28(5):383-398. (PMID: 29558289) Cell Death Differ. 2016 Mar;23(3):369-79. (PMID: 26794443) Stat Methods Med Res. 2013 Feb;22(1):57-69. (PMID: 21705438) FEBS J. 2022 Apr;289(7):1968-1983. (PMID: 34741776) J Cancer Res Clin Oncol. 2004 Jun;130(6):307-19. (PMID: 15034787) Onco Targets Ther. 2023 Jan 25;16:87-90. (PMID: 36721855) Phytother Res. 2015 Jul;29(7):969-77. (PMID: 25907962) Toxicol Appl Pharmacol. 2013 Oct 1;272(1):245-55. (PMID: 23707608) Case Reports Hepatol. 2020 Mar 10;2020:8247960. (PMID: 32231818) Front Pharmacol. 2021 Feb 01;12:620934. (PMID: 33597889) Jpn J Clin Oncol. 2014 Sep;44(9):872-5. (PMID: 24966207) Drug Des Devel Ther. 2021 Feb 12;15:543-556. (PMID: 33603344) Pharmacol Res. 2019 Jun;144:210-226. (PMID: 31022523) Cell. 2023 Jun 22;186(13):2748-2764.e22. (PMID: 37267948) Cell Death Dis. 2020 Feb 24;11(2):144. (PMID: 32094346) Hepatol Int. 2017 May;11(3):221-241. (PMID: 28405790) Nat Commun. 2020 Mar 2;11(1):1146. (PMID: 32123171) Signal Transduct Target Ther. 2022 Jun 20;7(1):196. (PMID: 35725836) Annu Rev Pharmacol Toxicol. 2022 Jan 6;62:279-300. (PMID: 34499527) Signal Transduct Target Ther. 2020 Jul 31;5(1):138. (PMID: 32732975) Bioorg Chem. 2022 Nov;128:106034. (PMID: 35908353) Nature. 2019 Nov;575(7784):688-692. (PMID: 31634900) Nature. 2015 Apr 2;520(7545):57-62. (PMID: 25799988) Cell Metab. 2020 May 5;31(5):956-968.e5. (PMID: 32213347) Cell. 2024 Jan 18;187(2):235-256. (PMID: 38242081) Cell Death Differ. 2022 Sep;29(9):1705-1718. (PMID: 35260822) Expert Opin Drug Discov. 2021 Dec;16(12):1497-1516. (PMID: 34294017) J Appl Toxicol. 2023 Mar;43(3):350-359. (PMID: 36008890) Hepatology. 2015 Mar;61(3):1066-79. (PMID: 25066777) Redox Biol. 2019 May;23:101107. (PMID: 30692038) Signal Transduct Target Ther. 2023 May 19;8(1):204. (PMID: 37208335) Gastroenterology. 2019 Jun;156(8):2230-2241.e11. (PMID: 30742832) Acta Pharmacol Sin. 2021 Jan;42(1):18-26. (PMID: 32144337) Drug Des Devel Ther. 2011;5:471-85. (PMID: 22162641) Redox Biol. 2021 Jan;38:101791. (PMID: 33197769) Cell Death Differ. 2022 May;29(5):895-910. (PMID: 35087226) J Exp Clin Cancer Res. 2024 Jan 13;43(1):19. (PMID: 38217037) |
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 |
تدمد: | 2041-4889 |
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DOI: | 10.1038/s41419-024-06993-z |