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The Hippo pathway is regulated by the cilium and has been suggested to be linked to NPH. The aim of the study was to investigate the involvement of Hippo pathway in the pathogenesis of\n                      <jats:italic>nphp1<\/jats:italic>\n                      defect\u2010associated NPH (NPH1).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Nphp1<\/jats:italic>\n                      knockout (\n                      <jats:italic>nphp1<\/jats:italic>\n                      <jats:sup>KO<\/jats:sup>\n                      ) Madin\u2010Darby Canine Kidney (MDCK) cells and\n                      <jats:italic>nphp1<\/jats:italic>\n                      <jats:sup>KO<\/jats:sup>\n                      C57BL\/6J mice were generated via CRISPR gene editing strategy. The siRNAs targeting\n                      <jats:italic>Kibra<\/jats:italic>\n                      ,\n                      <jats:italic>MST1<\/jats:italic>\n                      and\n                      <jats:italic>LATS1<\/jats:italic>\n                      were designed. An AAV9 vector was designed for\n                      <jats:italic>Kibra<\/jats:italic>\n                      knockdown. The expression and phosphorylation of core Hippo pathway molecules were evaluated. Pathological renal changes were evaluated via light microscopy respectively with haematoxylin\u2013eosin and Masson staining.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In\n                      <jats:italic>nphp1<\/jats:italic>\n                      <jats:sup>KO<\/jats:sup>\n                      MDCK cells,\n                      <jats:italic>nphp1<\/jats:italic>\n                      <jats:sup>KO<\/jats:sup>\n                      mice and NPH1 patients\u2019 kidneys, Kibra, p\u2010MST1\/2, p\u2010LATS and p\u2010YAP exhibited a notable increase in levels, with an even greater elevation observed in renal cyst cells, indicating the Hippo pathway activated in these\n                      <jats:italic>nphp1<\/jats:italic>\n                      \u2010deficient contexts.\n                      <jats:italic>Nphp1<\/jats:italic>\n                      re\u2010expression reversed the Hippo pathway activation in cells, indicating that the Hippo pathway activation is related to\n                      <jats:italic>nphp1<\/jats:italic>\n                      deficiency in vitro. Meanwhile, in vitro,\n                      <jats:italic>MST1<\/jats:italic>\n                      knockdown downregulated LATS1 and YAP phosphorylation,\n                      <jats:italic>LATS1<\/jats:italic>\n                      knockdown downregulated YAP phosphorylation, suggesting the activation of the canonical Hippo pathway in\n                      <jats:italic>nphp1<\/jats:italic>\n                      \u2010deficient contexts. Knockdown of the upstream regulator\n                      <jats:italic>Kibra<\/jats:italic>\n                      inhibited the Hippo pathway activation in both\n                      <jats:italic>nphp1<\/jats:italic>\n                      <jats:sup>KO<\/jats:sup>\n                      MDCK cells and mice. Following\n                      <jats:italic>Kibra<\/jats:italic>\n                      knockdown, the organisation of\n                      <jats:italic>nphp1<\/jats:italic>\n                      <jats:sup>KO<\/jats:sup>\n                      MDCK cells became more compact, the intensity of the actin fibres increased. Besides, decreased renal fibrosis and cyst formation were observed in\n                      <jats:italic>nphp1<\/jats:italic>\n                      <jats:sup>KO<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The canonical Hippo pathway is aberrantly activated in\n                      <jats:italic>nphp1<\/jats:italic>\n                      \u2010deficient conditions.\n                      <jats:italic>Kibra<\/jats:italic>\n                      may serve as a crucial upstream regulator of\n                      <jats:italic>nphp1<\/jats:italic>\n                      deficiency\u2010related Hippo pathway activation.\n                      <jats:italic>Kibra<\/jats:italic>\n                      upregulation and activation of the Hippo pathway are involved in the pathogenesis of NPH1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Canonical Hippo pathway activated in\n                            <jats:italic>nphp1<\/jats:italic>\n                            \u2010deficient disease models and patients.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Kibra was a key upstream molecule in regulating the activation of canonical Hippo pathway in\n                            <jats:italic>nphp1<\/jats:italic>\n                            \u2010deficient disease models and patients and closely related to renal cyst formation and fibrosis in\n     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