{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T03:11:41Z","timestamp":1793416301557,"version":"4.5.0"},"reference-count":61,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"794","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,4,16]]},"abstract":"<jats:p>\n            Cellular prion protein (PrP\n            <jats:sup>C<\/jats:sup>\n            ), known for its pathological isoform in prion diseases such as Creutzfeldt-Jakob disease, is primarily expressed in the nervous system but has also been detected in the blood and urine of individuals with renal dysfunction. However, the role of PrP\n            <jats:sup>C<\/jats:sup>\n            in the development of renal disease is unexplored. Here, we showed that PrP\n            <jats:sup>C<\/jats:sup>\n            was up-regulated in fibrotic renal lesions in biopsies from patients with chronic kidney disease (CKD), predominantly in proximal tubular epithelial cells (PTECs). Furthermore, renal expression of PrP\n            <jats:sup>C<\/jats:sup>\n            was positively correlated with the severity of renal failure and the decline in estimated glomerular filtration rate in patients with CKD. In mice, tubular-specific deletion of PrP\n            <jats:sup>C<\/jats:sup>\n            mitigated renal fibrosis induced by unilateral ureteral obstruction (UUO) or unilateral ischemia-reperfusion injury (UIRI). Mechanistically, PrP\n            <jats:sup>C<\/jats:sup>\n            was up-regulated by transforming growth factor\u2013\u03b21\u2013suppressor of mothers against decapentaplegic 3 signaling. PrP\n            <jats:sup>C<\/jats:sup>\n            activated TANK binding kinase 1 (TBK1)\u2013interferon regulatory factor 3 (IRF3) signaling through its capacity for liquid-liquid phase separation, which promoted a profibrotic response in PTECs and fibroblasts. Treating mice with amlexanox, a US Food and Drug Administration\u2013approved inhibitor of TBK1, either before the onset of renal fibrosis (in UUO and UIRI models) or after its establishment (in adenine- and aristolochic acid\u2013induced CKD models), mitigated worsening of renal fibrosis and renal function. Collectively, our findings uncovered a mechanism involving phase separation of PrP\n            <jats:sup>C<\/jats:sup>\n            underlying renal fibrosis and support further study of the PrP\n            <jats:sup>C<\/jats:sup>\n            -TBK1-IRF3 axis as a potential therapeutic target for CKD.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adj9095","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T18:00:51Z","timestamp":1744826451000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":21,"title":["Condensation of cellular prion protein promotes renal fibrosis through the TBK1-IRF3 signaling axis"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4731-9840","authenticated-orcid":true,"given":"Tantan","family":"Long","sequence":"first","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2519-8371","authenticated-orcid":true,"given":"Yumei","family":"Lu","sequence":"additional","affiliation":[{"name":"Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1587-4061","authenticated-orcid":true,"given":"Yuanyuan","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0659-1986","authenticated-orcid":true,"given":"Yandong","family":"Song","sequence":"additional","affiliation":[{"name":"Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Yi","sequence":"additional","affiliation":[{"name":"Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoliang","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengxin","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanmei","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyang","family":"Li","sequence":"additional","affiliation":[{"name":"Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, School of Basic Medical Sciences, University of South China, Hengyang 421001, China."},{"name":"Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China."},{"name":"Guangzhou Institute of Cancer Research, Affiliated Cancer Hospital, Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 510095, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3117-7418","authenticated-orcid":true,"given":"Fan Fan","family":"Hou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7466-1029","authenticated-orcid":true,"given":"Lirong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8887-9547","authenticated-orcid":true,"given":"Yupeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1002-5562","authenticated-orcid":true,"given":"Jing","family":"Nie","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China."},{"name":"Biobank of Peking University First Hospital, Peking University First Hospital, Beijing 100034, China."},{"name":"State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University Health Science Center, Beijing 100191, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.14745"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-024-00820-6"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)32064-5"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2023.01.021"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0235-9"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-061516-045115"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf4382"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.09.014"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2019.08.005"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006833"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012418-013109"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2007.06.019"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.3727\/000000003783992324"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0890-8508(02)00114-7"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-82-8-2017"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2430-3"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3148.2006.00662.x"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.01.002"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05769-3"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2016.48"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.71595"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00325"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1000-2"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2002521"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.10.009"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.7"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00857-2"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.054"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.211"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac194"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.06.006"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-022-02300-w"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.987979"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.02.023"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2017.00019"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.4161\/pri.3.3.9772"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-005-0128-6"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.607507"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0136923"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.4121"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015040449"},{"key":"e_1_3_2_43_2","first-page":"3018","article-title":"The 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