Pancreatic polypeptide interacts with neuropeptide Y4 receptor to promote hepatocellular carcinoma progression.

Pancreatic polypeptide (PP) and neuropeptide Y4 receptor (Y4R) are part of a conserved system that is involved in appetite regulation, gastrointestinal functions, and energy homeostasis. Experimental evidence suggests that PP-Y4R signaling might play a role in various extrahepatic cancer types, but the exact mechanisms remain unclear. Moreover, the potential role of PP-Y4R 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-derived tissues, which was correlated with a poor prognosis. Mechanistically, we found that PP promoted migration of HCC cells mediated via activation of extracellular signal-regulated kinase (ERK) signaling. Knockdown of Y4R or pharmacological inhibition of Y4R decreased migration, clonogenicity, and proliferation of HCC cells and induced a G1-cell cycle arrest and cellular senescence. Conversely, activation of the PP-Y4R axis was sufficient to overcome both spontaneous and sorafenib-induced senescence, which was mediated by ERK signaling. Our study provides novel insights into the pro-tumorigenic roles of PP and Y4R in HCC, indicating that PP-Y4R crosstalk might represent a potential novel therapeutic target. © 2026 The Pathological Society of Great Britain and Ireland.