{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T22:51:37Z","timestamp":1781736697362,"version":"3.54.5"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32160147"],"award-info":[{"award-number":["32160147"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32460152"],"award-info":[{"award-number":["32460152"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      TRPV4 is a non-selective cation channel of the TRPV family and plays a key role in fibrosis, but its pathological mechanisms in genetically susceptible individuals remain unclear. This study aimed to investigate the potential role of the\n                      <jats:italic>Trpv4<\/jats:italic>\n                      c.1491+1G&amp;gt;A splice-site mutation in pulmonary fibrosis using a gene-edited mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The mutation was identified in a family with autosomal dominant familial digital arthropathy-brachydactyly (FDAB). A corresponding gene-edited mouse model was generated using CRISPR\/Cas9 technology. Histopathological analysis, single-cell RNA sequencing (scRNA-seq), qPCR, Western blot, and immunofluorescence co-staining were employed to assess phenotypic, transcriptomic, and molecular changes in the lungs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The model mice exhibited skeletal abnormalities and multi-organ damage, with pronounced pulmonary fibrosis. In the lung tissues of homozygous mutant (\n                      <jats:italic>Trpv4<\/jats:italic>\n                      -Hom) mice, wild-type\n                      <jats:italic>Trpv4<\/jats:italic>\n                      expression was significantly reduced, accompanied by thickened alveolar septa, pulmonary congestion, and increased collagen deposition. scRNA-seq revealed a decrease in the proportions of alveolar macrophages and NK cells, while Clara cells, fibroblasts, mesothelial cells, and alveolar type II cells increased. The ALCAM-CD6 and MIF-CD74 signaling axes were significantly upregulated. qPCR confirmed the transcriptional upregulation of\n                      <jats:italic>Alcam<\/jats:italic>\n                      ,\n                      <jats:italic>Cd6<\/jats:italic>\n                      ,\n                      <jats:italic>Cd74<\/jats:italic>\n                      , and\n                      <jats:italic>Mif<\/jats:italic>\n                      ; Western blot further validated the increased protein levels of ALCAM, CD6, and CD74; and immunofluorescence confirmed the enhanced co-localization of MIF and CD74 in lung tissue.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>Trpv4<\/jats:italic>\n                      c.1491+1G&amp;gt;A mutation is associated with exacerbated pulmonary fibrosis, altered lung cellular composition, disrupted ALCAM-CD6 immune regulatory pathways and MIF signaling homeostasis, and enhanced pro-fibrotic cell communication. These findings provide novel molecular targets for the development of anti-fibrotic therapies targeting this pathway.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1834091","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T22:10:28Z","timestamp":1781734228000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Potential role of the Trpv4 c.1491+1G&gt;A mutation in pulmonary fibrosis in a gene-edited mouse model"],"prefix":"10.3389","volume":"17","author":[{"given":"Haolong","family":"Ruan","sequence":"first","affiliation":[{"name":"Engineering Research Center of Rare Disease Prevention and Control, University of Guangxi, Guilin Medical University","place":["Guilin, China"]},{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, Guilin Medical University","place":["Guilin, China"]},{"name":"School of Intelligent Medicine and 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