Targeting NPSR1-mediated Hippo-YAP1 dysregulation suppresses gastric cancer progression

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.