Integrative transcriptomic profiling links telomere dysfunction to cGAS–STING activation in heart failure signatures in mice and humans

AIMS: Cardiomyocyte telomere shortening is evident during heart failure pathogenesis. Conversely, mice with engineered telomerase deficiency develop myocardial dysfunction accompanied by p53 activation and mitochondrial repression. We aimed to address fundamental gaps in knowledge: whether cardiac dysfunction in mice lacking telomerase components arises from myocardial-intrinsic effects or systemic consequences of telomere shortening, which broader transcriptional programs follow, and what implications these have for clinical heart failure. METHODS AND RESULTS: We generated telomerase-deficient mice until generation 5 (mTRG5) and confirmed shortening telomeres along with increasing cardiac dysfunction by cardiovascular phenotyping and cardiomyocyte mitochondrial function assessment. Transcriptional and regulator analysis confirmed the telomere -p53 -mitochondria axis but extended beyond it, revealing additional involvement of neurohumoral activation, senescence, and inflammation, notably type I interferon signaling. To contextualize these findings, we compared this profile with hypertensive heart failure induced by neurohumoral dysregulation (angiotensin II infusion, nephrectomy, salt overload; ANS) and established a transcriptional hierarchy. In mTRG5 mice, regulators of telomere dysfunction and p53 activation ranked highest by significance and centrality, supporting telomere shortening as the primary upstream driver. Reciprocally, ANS mice showed higher-ranking neurohumoral regulators, indicating these govern secondary pathways. To pursue the strong type I interferon profile, we utilized myocardial profiles of mice lacking three-prime exonuclease 1, an established activator of the cGAS -STING pathway. Matching the profiles, we confirmed pronounced activation of cGAS -STING in mTRG5 mice -and slightly less in ANS mice -providing first evidence for cGAS -STING activation in telomere shortening and heart failure. Integration of the mTRG5 signature with curated transcriptomic datasets from murine and human dilated and ischemic cardiomyopathy revealed robust cross-species and cross-etiology overlap that increased with heart failure severity and decreased with functional recovery. CONCLUSION: These findings establish telomere dysfunction as a pathogenic driver that engages innate immune signaling via the cGAS -STING pathway, with direct relevance to human heart failure.