Promotion of hepatocellular carcinoma by small nuclear ribonucleoprotein polypeptide F through upregulation of transmembrane P24 trafficking protein 2 and triggering of the cGAS-STING pathway.

Spliceosome abnormalities are implicated in hepatocellular carcinoma (HCC) pathogenesis, but the role of the core component small nuclear ribonucleoprotein polypeptide F (SNRPF) remains unclear. This study aims to elucidate the role and mechanism of SNRPF in HCC progression. SNRPF expression and clinical significance were analyzed using the DepMap and TCGA databases, alongside clinical HCC specimens. The results revealed that SNRPF was essential for HCC cell proliferation (CERES score = -3.02) and aberrantly overexpressed in HCC, correlating with poor prognosis. Functional validation via overexpression or knockdown in HCC cells demonstrated that SNRPF significantly promoted HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition. Mechanistically, RNA immunoprecipitation and reporter gene assays showed SNRPF bound to the pre-mRNA of transmembrane P24 trafficking protein 2 (TMED2), preventing its Intron 2 retention and subsequent nonsense-mediated decay, thereby ensuring TMED2 protein abundance. Co-immunoprecipitation and GST pull-down assays revealed that TMED2 directly interacted with cGAS, promoting its activation and the subsequent STING/TBK1/IRF3 signaling cascade. This activation induced elevated levels of IFN-β, ISG15, and IFIT1/2, as well as the secretion of IFN-β, TNF-α, and IL-6. Rescue experiments using cGAS or STING inhibitors confirmed these findings. In vivo experiments using an orthotopic xenograft tumor model in mice further confirmed that the SNRPF/TMED2/cGAS-STING axis significantly promotes the growth and progression of HCC tumors. In conclusion, this study elucidates the pivotal oncogenic function of the SNRPF/TMED2/cGAS-STING signaling axis in HCC, providing novel strategies for prognosis prediction and targeted therapy.