Abstract

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and predominantly affects older individuals, yet effective treatments remain limited. The molecular mechanisms linking cardiac aging to HFpEF are not fully understood. Here we show that the transcriptional regulator Sub1 is upregulated in aged hearts and in mouse models of HFpEF. Cardiac overexpression of Sub1 shortens lifespan, exacerbates diastolic dysfunction, and accelerates cardiac aging, whereas Sub1 knockdown delays cardiac aging and alleviates HFpEF features, even when initiated in aged mice. Mechanistically, Sub1 interacted with TAF9b and AROS to stabilize p53 by regulating its ubiquitination and acetylation, thereby promoting cardiomyocyte senescence. Furthermore, disrupting the Sub1–p53 interaction attenuates cardiomyocyte senescence in vitro. These findings identify Sub1 as a contributor to aging-associated HFpEF and provide insight into the molecular links between cardiac aging and disease progression. Heart failure with preserved ejection fraction (HFpEF) predominantly affects older individuals. Here the authors report that the transcriptional regulator Sub1 promotes age-related HFpEF in mice, potentially via stabilizing p53 and subsequent cardiomyocyte senescence.