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Experimental evidence suggests that PP\u2010Y4R signaling might play a role in various extrahepatic cancer types, but the exact mechanisms remain unclear. Moreover, the potential role of PP\u2010Y4R crosstalk in hepatocellular carcinoma (HCC) was unknown and has been addressed in this study. We found that the ligand (PP) and the receptor (Y4R) were markedly overexpressed in HCC cells and in patient\u2010derived tissues, which was correlated with a poor prognosis. Mechanistically, we found that PP promoted migration of HCC cells mediated via activation of extracellular signal\u2010regulated kinase (ERK) signaling. Knockdown of\n                    <jats:italic>Y4R<\/jats:italic>\n                    or pharmacological inhibition of Y4R decreased migration, clonogenicity, and proliferation of HCC cells and induced a G1\u2010cell cycle arrest and cellular senescence. Conversely, activation of the PP\u2010Y4R axis was sufficient to overcome both spontaneous and sorafenib\u2010induced senescence, which was mediated by ERK signaling. Our study provides novel insights into the pro\u2010tumorigenic roles of PP and Y4R in HCC, indicating that PP\u2010Y4R crosstalk might represent a potential novel therapeutic target. \u00a9 2026 The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70115","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:44:10Z","timestamp":1787129050000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pancreatic polypeptide interacts with neuropeptide\n                    <scp>Y4<\/scp>\n                    receptor to promote hepatocellular carcinoma progression"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3872-7104","authenticated-orcid":false,"given":"Laura","family":"Wormser","sequence":"first","affiliation":[{"name":"Institute of Biochemistry Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg  Erlangen Germany"},{"name":"Department of Medicine 1 University Hospital Erlangen, Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Kojic","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg  Erlangen Germany"},{"name":"Department of Medicine 1 University Hospital Erlangen, Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5441-7821","authenticated-orcid":false,"given":"Valerie","family":"Fritz","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg  Erlangen Germany"},{"name":"Department of Medicine 1 University Hospital Erlangen, 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Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg and Universit\u00e4tsklinikum Erlangen  Erlangen Germany"},{"name":"Comprehensive Cancer Center Erlangen\u2010European Metropolitan Region Nuremberg  Erlangen Germany"},{"name":"Bavarian Center for Cancer Research (BZKF)  Erlangen Germany"},{"name":"European Reference Network for Rare Hepatological Diseases Universit\u00e4tsklinikum Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7028-3881","authenticated-orcid":false,"given":"Jonel","family":"Trebicka","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine B University of M\u00fcnster  M\u00fcnster Germany"},{"name":"European Foundation for the Study of Chronic Liver Failure  Barcelona 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