{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:24:03Z","timestamp":1787747043628,"version":"build-2784847793"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"crossref","award":["2021R1A2C2011292"],"award-info":[{"award-number":["2021R1A2C2011292"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"crossref","award":["23B0104L1"],"award-info":[{"award-number":["23B0104L1"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2026,7]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n Targeting METTL3 with the heat shock protein 90 inhibitor 17-DMAG mitigated kidney fibrosis in CKD.<\/jats:p>\n <\/jats:list-item>\n \n The drug repositioning through differentially expressed gene and enrichment analyses identified 17-dimethylaminoethylamino-17-demethoxygeldanamycin as a potential agent to alleviate kidney fibrosis.<\/jats:p>\n <\/jats:list-item>\n \n \n The\n N<\/jats:italic>\n -terminal heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin suppressed c-Jun\u2013METTL3 signaling, attenuating\n N<\/jats:italic>\n 6-methyladenosine methylation and kidney fibrosis.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n Kidney fibrosis is a major pathological feature of CKD, characterized by excessive deposition of extracellular matrix proteins, leading to progressive loss of kidney function.\n N<\/jats:italic>\n 6-methyladenosine (m6A) RNA methylation has emerged as a crucial epigenetic modification implicated in various diseases, including kidney fibrosis. METTL3, an m6A writer, plays a key role in promoting fibrosis by stabilizing profibrotic gene expression. Therefore, targeting METTL3 represents a promising therapeutic strategy for CKD treatment. In this study, we explored the therapeutic potential of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in regulating METTL3 to mitigate kidney fibrosis.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Through transcriptome-based drug repositioning, we identified 17-DMAG as a potential inhibitor of METTL3. Differentially expressed gene analysis was performed to assess the enrichment of 17-DMAG in CKD-related gene expression profiles. The antifibrotic effects of 17-DMAG were evaluated in\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n models. The mechanism by which 17-DMAG downregulates METTL3 was also investigated.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n 17-DMAG significantly reduced METTL3 expression in renal epithelial cells in a dose-dependent and time-dependent manner. In\n in vivo<\/jats:italic>\n mouse models of kidney fibrosis, 17-DMAG treatment attenuated METTL3 levels, reduced total m6A modification, and effectively mitigated fibrosis, as evidenced by decreased collagen deposition and profibrotic marker expression. Mechanistically, 17-DMAG, a heat shock protein 90 (HSP90)\n N<\/jats:italic>\n -terminal inhibitor, induced a heat shock response that sequentially upregulated HSP70 expression. The elevated HSP70 levels inhibited c-Jun\n N<\/jats:italic>\n -terminal kinase activity, thereby suppressing the c-Jun transcription factor and ultimately leading to the downregulation of METTL3 expression. MeRIP-Seq analysis revealed that 17-DMAG reversed unilateral ischemia-reperfusion injury\u2013induced m6A epitranscriptomic changes in fibrosis-related genes, including\n GSK3B<\/jats:italic>\n , which is involved in fibrotic pathways.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n N<\/jats:italic>\n -terminal HSP90 inhibition, along with subsequent c-Jun suppression, contributed to the mechanism underlying 17-DMAG\u2013induced METTL3 downregulation. Through this regulatory pathway, 17-DMAG effectively suppressed METTL3 expression and attenuated kidney fibrosis in both\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n models.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.0000000975","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T17:00:16Z","timestamp":1769446816000},"page":"1404-1422","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":3,"title":["Therapeutic Potential of Heat Shock Protein 90 Inhibitor 17-DMAG in Regulating METTL3 for Kidney Fibrosis Treatment"],"prefix":"10.1681","volume":"37","author":[{"given":"Soo Min","family":"Lee","sequence":"first","affiliation":[{"name":"College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea"},{"name":"Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5285-4874","authenticated-orcid":false,"given":"Myoung Seok","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Radiology, Seoul National University Boramae Medical Center, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8307-2474","authenticated-orcid":false,"given":"Hae Rim","family":"Jung","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3199-635X","authenticated-orcid":false,"given":"Jeonghwan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea"},{"name":"Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogyeong","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3640-0914","authenticated-orcid":false,"given":"Wencheng","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea"},{"name":"Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2448-2895","authenticated-orcid":false,"given":"Min Hoan","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Radiology, Seoul National University Boramae Medical Center, Seoul, Republic of Korea"},{"name":"Department of Radiology, Seoul National University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9603-5077","authenticated-orcid":false,"given":"Nayeon","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5132-5452","authenticated-orcid":false,"given":"Seung Hyun","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da Som","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bada","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea"},{"name":"Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6033-290X","authenticated-orcid":false,"given":"Seung-Pyo","family":"Hong","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong-Il","family":"Kim","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea"},{"name":"Cancer Research Institute, Seoul National University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9123-6542","authenticated-orcid":false,"given":"Chun Soo","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea"},{"name":"Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2720-6952","authenticated-orcid":false,"given":"Sung-Yup","family":"Cho","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea"},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea"},{"name":"Cancer Research Institute, Seoul National University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Woo","family":"Choi","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea"},{"name":"Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, Republic of Korea"},{"name":"Department of Pharmacology, Institute of Regulatory Innovation Through Science, Kyung Hee University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4714-1260","authenticated-orcid":false,"given":"Jung Pyo","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea"},{"name":"Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,1,26]]},"reference":[{"issue":"5","key":"B1-20260826","doi-asserted-by":"crossref","first-page":"586","DOI":"10.23876\/j.krcp.23.156","article-title":"Pathogenesis and management of renal fibrosis induced by unilateral ureteral obstruction","volume":"43","author":"Nan","year":"2024","journal-title":"Kidney Res Clin 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