Shelterin Component TPP1 Drives Tumor Progression and Predicts Poor Prognosis in Hepatocellular Carcinoma

Background/Objectives: Telomere dysfunction and the shelterin complex are implicated in cancer, yet the specific functions and interactions of telomerase and shelterin genes in hepatocellular carcinoma (HCC) tumorigenesis remain poorly understood. This study aims to investigate the clinico-biological functions and collaborative contributions of telomerase and shelterin components in hepatocarcinogenesis. Methods: We analyzed tumor and matched non-tumor tissues from 274 HCC patients who underwent hepatectomy. Telomere-related parameters, including TERT (telomerase reverse transcriptase) expression and telomere length measured by qRT-PCR, telomerase activity assessed by the Telomerase Repeated Amplification Protocol assay, and six shelterin components analyzed by RNA sequencing, were correlated with clinicopathological features. siRNA-mediated knockdown of TPP1 (POT1–TIN2 organizing protein) was performed to evaluate its regulatory effect on TERT expression. Findings were externally validated. Results: TERT and TPP1 were upregulated in tumors with increased telomerase activity and shortened telomere length. Among the shelterin components, TPP1 showed the strongest correlation with TERT, and its expression increased with tumor multiplicity and advancing stage. TPP1 expression also correlated with proliferation-associated genes, consistent with Gene Set Enrichment Analysis suggesting TPP1 involvement in proliferative activity. TPP1 knockdown suppressed TERT protein expression and inhibited HCC cell proliferation, with the strongest anti-proliferative effect observed after dual TERT–TPP1 knockdown. Clinically, high TPP1 expression was associated with significantly earlier HCC recurrence, and co-high expression of TPP1–TERT was linked to significantly worse survival after hepatectomy. Conclusions: The TERT–TPP1 axis enhances proliferative activity and is associated with aggressive features and poor outcomes in HCC. TPP1 represents a potential therapeutic target and prognostic biomarker for HCC.