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Neuropilin-1 (NRP1) has been identified as a co-receptor involved in multiple signaling pathways, yet its role in modulating TGF-\u03b2 receptor stability in HSCs remains to be fully elucidated. This study investigated the regulatory role of the NRP1\/Src\/Rab7 axis in T\u03b2RI lysosomal degradation during HSC activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Hepatic fibrosis was induced in male C57BL\/6 mice via intraperitoneal CCl\n                      <jats:sub>4<\/jats:sub>\n                      injection for four weeks. HSC-specific knockdown of\n                      <jats:italic>Nrp1<\/jats:italic>\n                      was achieved using an AAV8-pLrat-sh\n                      <jats:italic>Nrp1<\/jats:italic>\n                      vector. T\u03b2RI stability and lysosomal degradation were evaluated through cycloheximide (CHX) chase assays and chloroquine treatment. The impact on the TGF-\u03b21\/Smad signaling pathway was assessed both in vitro and in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Nrp1<\/jats:italic>\n                      silencing in primary HSCs reduced T\u03b2RI protein levels and attenuated p-Smad2\/3 signaling without affecting mRNA levels. Consistently, NRP1 deficiency accelerated lysosomal degradation of T\u03b2RI, accompanied by increased T\u03b2RI\u2013LAMP1 colocalization and enhanced trafficking of T\u03b2RI into Rab7-positive late endosomes. Mechanistically, NRP1 loss diminished Src kinase activity and consequently reduced Src-dependent tyrosine phosphorylation of Rab7, leading to elevated Rab7-GTP levels and enhanced late endosomal sorting of T\u03b2RI.\n                      <jats:italic>Rab7<\/jats:italic>\n                      knockdown or Src reactivation partially rescued T\u03b2RI stability and restored downstream signaling. In vivo, HSC-specific\n                      <jats:italic>Nrp1<\/jats:italic>\n                      knockdown attenuated CCl\n                      <jats:sub>4<\/jats:sub>\n                      -induced fibrosis and reduced T\u03b2RI levels, while Rab7 inhibition partially reversed these effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data suggest that the NRP1\/Src\/Rab7 axis contributes to T\u03b2RI stability by modulating its lysosomal degradation pathway. Targeting this axis may provide a potential approach for intervening in the progression of hepatic fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41420-026-03220-w","type":"journal-article","created":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:55:06Z","timestamp":1782608106000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NRP1 promotes hepatic fibrosis by regulating Src\/Rab7-mediated lysosomal degradation of T\u03b2RI"],"prefix":"10.1038","volume":"12","author":[{"given":"Zhe","family":"Jia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,28]]},"reference":[{"key":"3220_CR1","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1146\/annurev-pathol-011110-130246","volume":"6","author":"V Hernandez-Gea","year":"2011","unstructured":"Hernandez-Gea V, Friedman SL. 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