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Neutrophil extracellular traps (NETs) are complex web\u2010like structures released by activated neutrophils, but their functional contribution to CKD\u2013TIF remains largely unknown. Here, we uncovered a novel pathological role of NETs in driving TIF development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>NETs levels were evaluated in human kidney biopsies and serum samples. Peptidylarginine deiminase 4 (PAD4) knockout mice were subjected to unilateral ureteral obstruction and adenine\u2010induced nephropathy models. The underlying mechanisms were elucidated by RNA sequencing, transmission electron microscopy, molecular docking and co\u2010immunoprecipitation. The PAD4 inhibitor GSK484 was administered to evaluate the role of NETs in TIF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>NETs markedly accumulated in kidneys of CKD patients and murine models, positively correlating with renal dysfunction and fibrosis progression. PAD4 knockout suppressed NETs formation and attenuated TIF. Mechanistically, transcriptomic analyses displayed pronounced activation of autophagy\u2010related pathways in NETs\u2010stimulated fibroblasts, whereas autophagy inhibition suppressed fibroblast activation. NETs components interacted with the transmembrane receptor coiled\u2010coil domain\u2010containing protein 25 (CCDC25), triggering dissociation of Yes\u2010associated protein 1 (YAP1) from its receptor. This molecular rearrangement facilitates YAP1 nuclear translocation, subsequently enhancing autophagic activity in fibroblasts and promoting their phenotypic transition into myofibroblasts. Therapeutic administration of the PAD4 inhibitor GSK484 significantly attenuated renal fibrosis in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Our study provides the first evidence that NETs exacerbate CKD\u2013TIF by enhancing fibroblast autophagy via the CCDC25\u2013YAP1 axis, highlighting the NETs inhibitor GSK484 as a promising therapeutic candidate.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70524","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T06:11:13Z","timestamp":1779948673000},"page":"5190-5210","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Neutrophil extracellular traps drive tubulointerstitial fibrosis via the coiled\u2010coil domain\u2010containing protein 25 (CCDC25)\u2013Yes\u2010associated protein 1 (YAP1) axis\u2010mediated autophagy regulation"],"prefix":"10.1111","volume":"183","author":[{"given":"Xinhui","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Clinical Nutrition, Zhongda Hospital, School of Medicine Southeast University  Nanjing Jiangsu China"},{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine Southeast University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijie","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine Southeast University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine Nanjing Medical University  Taizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6694-8406","authenticated-orcid":false,"given":"Zuolin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine Southeast University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3715-1174","authenticated-orcid":false,"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine Southeast University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine Southeast University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine Southeast University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital, School of Medicine Southeast University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyuan","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine Nanjing Medical University  Taizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"issue":"2","key":"e_1_2_11_2_1","first-page":"S289","article-title":"The concise guide to pharmacology 2023\/24: Enzymes","volume":"180","author":"Alexander S. 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