Non-Telomeric Role of RAP1 in Facilitating NF-κB Activation and Driving Hepatocellular Carcinoma Progression

RAP1 (TERF2IP) is a component of the shelterin complex that protects telomeric DNA and preserves chromosome stability. In addition to its telomeric function, accumulating evidence indicates that mammalian RAP1 also exerts multiple extra-telomeric functions. Notably, RAP1 has been reported to regulate the NF-κB signaling pathway and to function as a transcriptional regulator, suggesting potential roles in tumorigenesis. In this study, we found that RAP1 expression was significantly upregulated in hepatocellular carcinoma (HCC) cells. Functional analyses demonstrated that RAP1 promoted malignant phenotypes in HCC through a non-telomeric mechanism. In cellular models, RAP1 overexpression enhanced cell proliferation while suppressing senescence and apoptosis, whereas RAP1 knockdown produced the opposite effects. Mechanistically, RAP1 functioned as an upstream activator of the NF-κB signaling cascade, resulting in increased phosphorylation of the p65 subunit and upregulation of downstream targets, including IL-1β and BCL-2. Importantly, the oncogenic activity of RAP1 was shown to be dependent on NF-κB signaling in vivo, as pharmacological inhibition of NF-κB significantly suppressed RAP1-driven tumor growth in a xenograft model. Collectively, these findings reveal a previously unrecognized role for RAP1 in promoting HCC progression through activation of NF-κB signaling and identify the RAP1/NF-κB axis as a potential therapeutic target for HCC.