{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:33:10Z","timestamp":1792787590826,"version":"4.5.0"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["92581124"],"award-info":[{"award-number":["92581124"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["82470770"],"award-info":[{"award-number":["82470770"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["82470769"],"award-info":[{"award-number":["82470769"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Young Scholars of Yangtze River Scholar Professor Program","award":["2023"],"award-info":[{"award-number":["2023"]}]},{"name":"Jiangsu Provincial Key Research and Development Program","award":["BE2023770"],"award-info":[{"award-number":["BE2023770"]}]},{"name":"Jiangsu Province High-Level Hospital Construction Funds of Zhongda Hospital, School of Medicine, Southeast University","award":["GSP-JCYJ-01"],"award-info":[{"award-number":["GSP-JCYJ-01"]}]},{"name":"Research Personnel Cultivation Programme of Zhongda Hospital Southeast University","award":["CZXM-GSP-RC150"],"award-info":[{"award-number":["CZXM-GSP-RC150"]}],"id":[{"id":"https:\/\/ror.org\/01k3hq685","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Zhongda Hospital Affiliated to Southeast University, Jiangsu Province High-Level Hospital Construction Funds","award":["GSP-LCYJFH08"],"award-info":[{"award-number":["GSP-LCYJFH08"]}]},{"name":"Zhongda Hospital Affiliated to Southeast University, Jiangsu Province High-Level Hospital Pairing Assistance Construction Funds","award":["zdlyg02"],"award-info":[{"award-number":["zdlyg02"]}]},{"name":"Fundamental Research Funds for the Central Universities","award":["2242024k30041"],"award-info":[{"award-number":["2242024k30041"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"\n Missense mutations in the\n UMOD<\/jats:italic>\n gene are a well-established genetic cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). Here, we report two ADTKD pedigrees carrying de novo UMOD mutations, p.His36Tyr (H36Y) and p.Trp31Cys (W31C). To elucidate the underlying pathogenic mechanisms and explore targeted therapeutic strategies, we generated a UMOD\n H36Y\/+<\/jats:sup>\n knock-in mouse model using CRISPR\/Cas9 technology, which recapitulated the major clinical manifestations observed in patients. Through single-cell RNA sequencing and experimental validation, we demonstrated that uromodulin mutations triggered endoplasmic reticulum (ER) stress and the unfolded protein response, with ferroptosis identified as the predominant mode of cell death in this disease. These findings were further confirmed in plasmid-transfected cell models expressing UMOD\n H36Y<\/jats:sup>\n and UMOD\n W31C<\/jats:sup>\n . Moreover, the molecular chaperone HSPA1A was identified as a potential therapeutic target. Geranylgeranylacetone, targeting HSPA1A as a chaperone drug, effectively mitigated endoplasmic reticulum stress, alleviated ferroptosis, and delayed the progression of renal dysfunction. Based on novel uromodulin mutations, our study reveals a pathogenic ER-ferroptosis axis in ADTKD-\n UMOD<\/jats:italic>\n , deepens the insight into the pathogenesis of ADTKD-\n UMOD<\/jats:italic>\n , and provides a promising strategy for developing chaperone therapy with drug repurposing in genetic kidney diseases.\n <\/jats:p>","DOI":"10.1172\/jci.insight.207210","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:01:33Z","timestamp":1791302493000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting HSPA1A with geranylgeranylacetone alleviates ADTKD-UMOD via suppression of endoplasmic reticulum stress and ferroptosis"],"prefix":"10.1172","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2115-6157","authenticated-orcid":true,"given":"Wen","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, Southeast University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianli","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxuan","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyuan","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, Southeast University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bi-Cheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, Southeast University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, Southeast University, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,10,6]]},"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/insight.jci.org\/articles\/view\/207210\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:01:34Z","timestamp":1791302494000},"score":1,"resource":{"primary":{"URL":"http:\/\/insight.jci.org\/articles\/view\/207210"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,6]]},"references-count":0,"alternative-id":["10.1172\/jci.insight.207210"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.207210","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,6]]}}}