TERT drives liver tumorigenesis beyond telomere elongation.

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 mo of age, ∼15% 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 HrasGln61Lys 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, whereas MAPK-mutated tumors showed profiles consistent with MAPK/ERK pathway activation. All HCCs suppressed the gluconeogenic genes Fbp1 and AldoB, but diverged into two distinct groups based on their glycolytic and NRF2 target gene expression profiles. 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.