Oncogenic GPRIN1 sustains proliferation and mitochondrial homeostasis via dual‑layer CDK1-PI3K/Akt signalling in...

Novel therapeutic targets are urgently needed for the aggressive malignancy gallbladder cancer (GBC). G-protein regulated inducer of neurite outgrowth 1 (GPRIN1) is a candidate oncogene, but its function in GBC and its connection to mitochondrial dysregulation remain unknown. In this study, we analyzed clinical samples and demonstrated that GPRIN1 is significantly upregulated in GBC tissues, where its high expression correlates with advanced clinical stage and poor patient prognosis. Functional assays revealed that GPRIN1 is essential for GBC progression, driving cell cycle advancement and maintaining mitochondrial homeostasis. By integrating proteomic and molecular analyses, our study delineates a bimodal and hierarchical regulatory program commanded by GPRIN1 to ensure the robust activation of CDK1. In the nucleus, GPRIN1 functions as a transcriptional co-activator, scaffolding and stabilizing E2F1 to drive CDK1 expression. In parallel, it functions at a post-translational level to directly promote CDK1 activation by physically steering the kinase away from its inhibitor, MYT1, and toward its activator, Cdc25C. This dual-pronged regulation culminates in hyperactivated CDK1, which in turn unleashes a PI3K-Akt signaling cascade to couple relentless cell proliferation with the necessary mitochondrial support. Importantly, genetic or pharmacological disruption of this GPRIN1-CDK1-PI3K/Akt axis completely abrogated tumorigenesis in vitro and in vivo. Taken together, these results reveal GPRIN1 as a master regulator whose dual transcriptional and post-translational control of CDK1 integrates cell cycle progression with mitochondrial homeostasis, suggesting that targeting GPRIN1 may represent a highly specific therapeutic strategy in this lethal malignancy.