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Early-onset and progressive renal tubulointerstitial fibrosis represents one of the most significant features, culminating in renal insufficiency. However, the molecular mechanism of tubulointerstitial fibrosis remains unclear. Previously, we constructed an NPH mouse model via CRISPR-Cas9. This mouse model demonstrated typical features of tubulointerstitial fibrosis. In this study, we aimed to explore the pathogenesis of tubulointerstitial fibrosis in NPH and identify early intervention targets in both the NPH models and patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, transcriptome changes in mouse kidneys were analyzed through RNA sequencing to explore the molecular mechanisms of renal tubulointerstitial fibrosis in NPH. We found an increased abundance of calpain1 in both the NPH models and patients. Pathway enrichment analysis indicated autophagy-lysosomal pathway was altered in the NPH models. Western blot, immunofluorescence or immunohistochemical staining were used to verify the expression of calpain1. We also detected autophagy activities in NPH models by lysotracker staining and transmission electron microscopy (TEM). Epithelial or mesenchymal-specific markers and Masson\u2019s trichrome staining were used to detect the status of tubulointerstitial fibrosis. Furthermore, NPH models were treated with a calpain1 inhibitor to explore the role of calpain1 in autophagy-lysosomal pathway and tubulointerstitial fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The increased abundance of calpain1 impaired the autophagy-lysosomal pathway and induced tubulointerstitial fibrosis by promoting epithelial-to-mesenchymal transition. On the other hand, calpain1 inhibition could enhance the autophagy-lysosomal pathway and ameliorate the phenotypes of tubulointerstitial fibrosis in NPH models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Calpain1-mediated autophagy-lysosomal pathway disorder may be an important cause of tubulointerstitial fibrosis in NPH. Calpain1 may have therapeutic implications for renal tubulointerstitial fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-025-01231-4","type":"journal-article","created":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T11:55:19Z","timestamp":1746273319000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Calpain1 inhibition enhances autophagy-lysosomal pathway and ameliorates tubulointerstitial fibrosis in Nephronophthisis"],"prefix":"10.1186","volume":"31","author":[{"given":"Dantong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinglan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayong","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoya","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huamu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangzhong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,3]]},"reference":[{"issue":"9","key":"1231_CR36","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1038\/cdd.2012.46","volume":"19","author":"T Arnandis","year":"2012","unstructured":"Arnandis T, Ferrer-Vicens I, Garc\u00eda-Trevijano ER, et al. 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All recruited subjects agreed to participate in the experiment and signed the consent form. Research involving human data was approved by Guangdong Provincial People's Hospital (Ethics Approval Number: S2023-010\u201301). All animals were maintained according to the ARRIVE1 guidelines, and all protocols for animal use and euthanasia were reviewed and approved by the Institutional Animal Care and Use Committee of Nanfang Hospital, Southern Medical University (Ethics Approval Number: IACUC-LAC-20220723\u2013001).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Consent for publication was obtained from the patients mentioned in this study. Copies of consent forms could be sent upon request.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"166"}}