TERT drives liver tumorigenesis beyond telomere elongation

Abstract We generated two mouse models, p21 ⁺/Tert and p21 ⁺/TertCi , expressing either telomerase reverse transcriptase (TERT) or a catalytically inactive variant under the control of the p21 promoter. By 18–20 months of age, approximately 25% of mice from both genotypes developed liver tumors with histopathological features resembling human hepatocellular carcinoma (HCC). Whole-exome sequencing identified activating Ctnnb1 mutations and recurrent PP1 subunit alterations in p21 ⁺/Tert tumors, whereas p21 ⁺/TertCi tumors harbored activating Hras Gln61Lys mutations associated with elevated C>A transversions. Both models exhibited chromosomal aberrations commonly observed in human HCC. Transcriptomic analyses revealed that β-catenin–activated tumors recapitulated gene expression signatures of human HCC, while MAPK-mutated tumors showed profiles consistent with MAPK/ERK pathway activation. Metabolically, both genotypes demonstrated increased glycolysis and suppression of gluconeogenesis, including downregulation of FBP1, but expressed distinct NRF2 target genes. Spatial profiling further revealed reduced HNF4α-positive hepatocytes across tumors, independent of Hnf4α transcription, and markedly diminished immune cell infiltration particularly in β-catenin–activated tumors. Collectively, these findings uncover telomere-independent functions of TERT and identify molecular and metabolic features with potential relevance for predicting immunotherapy response.