SNRPC ‐ DHX9 ‐ RelA Complex Drives Cell‐Cycle Signaling and CDK4 /6 Inhibitor Sensitivity in Hepatocellular Carcinoma

ABSTRACT SNRPC is a core spliceosomal protein, but its oncogenic function and therapeutic relevance in hepatocellular carcinoma (HCC) remain incompletely defined. Here, we found that SNRPC was upregulated in HCC tissues and was associated with adverse clinicopathological features and poor survival. In the TCGA‐LIHC cohort, high SNRPC expression remained associated with poorer overall survival after multivariable adjustment. Gain‐ and loss‐of‐function studies showed that SNRPC promoted HCC cell proliferation and migration in vitro and tumor growth in vivo. Mechanistically, SNRPC interacted with DHX9 and RelA/p65 to form a functional complex that enhanced NF‐κB signaling and downstream CDK4/6‐E2F1 signaling. Mutational analysis showed that the ATP‐binding residue K417 of DHX9 contributed to RelA/p65 Ser536 phosphorylation, supporting a functional role for DHX9 in this signaling complex. Consistently, SNRPC or DHX9 depletion altered cell‐cycle distribution and reduced NF‐κB‐associated cell‐cycle signaling. Finally, the CDK4/6 inhibitor palbociclib markedly suppressed the enhanced growth of SNRPC‐ or DHX9‐overexpressing xenografts. These findings identify a non‐canonical oncogenic function of SNRPC in HCC and provide a mechanistic rationale for further evaluating CDK4/6 inhibition in tumors characterized by activation of the SNRPC/DHX9 signaling network.