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Mol. Life Sci."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The targeting of G protein-coupled receptors (GPCRs) has emerged as a promising strategy for developing novel cancer therapies. Moreover, inactivation of the Hippo signaling pathway is recognized as a critical driver of gastric cancer (GC) progression. However, the precise molecular mechanisms underlying cross-talk between GPCRs and the Hippo pathway remain to be further investigated. Here, we identify NPSR1 as an oncogenic driver promoting GC advancement. NPSR1 is significantly overexpressed in GC tissues and negatively correlates with patient prognosis. Both in vivo and in vitro studies demonstrated that NPSR1 overexpression robustly accelerated GC cell proliferation and migration, while its silencing suppressed tumor progression. Mechanistically, our findings revealed a dual regulatory axis: (i) NPSR1 activated the cAMP\/CREB pathway to enhance YAP1 transcription; and (ii) it directly facilitated phosphatase PP2Ac expression, thereby reducing YAP1 phosphorylation. This promotes the translocation of YAP1 from the cytoplasm to the nucleus, enhancing its oncogenic function. Our study uncovers a novel molecular link between NPSR1 hyperactivation and Hippo pathway suppression through coordinated transcriptional upregulation and post-translational modulation of YAP1. These results highlight NPSR1 as a potential therapeutic target for GC, offering a rationale for developing targeted inhibitors to restore Hippo signaling.<\/jats:p>","DOI":"10.1007\/s00018-026-06181-6","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T10:35:26Z","timestamp":1775730926000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting NPSR1-mediated Hippo-YAP1 dysregulation suppresses gastric cancer progression"],"prefix":"10.1007","volume":"83","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8733-8759","authenticated-orcid":false,"given":"Wenjing","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4656-3752","authenticated-orcid":false,"given":"Mei","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidan","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1567-8415","authenticated-orcid":false,"given":"Bin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"6181_CR1","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/S0140-6736(20)31288-5","volume":"396","author":"EC Smyth","year":"2020","unstructured":"Smyth EC, Nilsson M, Grabsch HI, Van Grieken NC, Lordick F (2020) Gastric cancer. 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Nature 445:53\u201357. https:\/\/doi.org\/10.1038\/nature05351","journal-title":"Nature"}],"container-title":["Cellular and Molecular Life Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00018-026-06181-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-026-06181-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-026-06181-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T21:40:38Z","timestamp":1781646038000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00018-026-06181-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,9]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["6181"],"URL":"https:\/\/doi.org\/10.1007\/s00018-026-06181-6","relation":{},"ISSN":["1420-9071"],"issn-type":[{"value":"1420-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,9]]},"assertion":[{"value":"13 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 December 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 December 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 April 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experimental procedures in this study were conducted in strict compliance with internationally recognized ethical standards, including the guidelines established by the Responsible Committee on Human Experimentation and the principles outlined in the Helsinki Declaration. Specifically, the protocols for the collection, handling, and use of clinical samples were reviewed and formally approved by the Institutional Ethics Committee of Outdo Biotech Co., Ltd. (Shanghai, China; Approval No.: SHYJS-CP-1807022). Additionally, all animal experiments were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University (Approval No.: CDYFY-IUC-202502GR011), ensuring adherence to ethical standards for animal welfare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors consent to publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"217"}}