AIMS: In this study, we aimed to uncover genes associated with stressed cardiomyocytes by combining single-cell transcriptomic data sets from failing cardiac tissue from both humans and mice. METHODS AND RESULTS: Our bioinformatic analysis identified SORBS2 as conserved NPPA-correlated gene. Using mouse models and cardiac tissue from human heart failure patients, we demonstrated that SORBS2 expression is consistently increased during pathological remodelling, correlates to disease severity, and is regulated by GATA4. By affinity purification mass spectrometry, we showed SORBS2 to interact with the integrin-cytoskeleton connections. Cardiomyocyte-specific genetic loss of Sorbs2 in adult mice changed integrin interactions, indicated by the increased expression of several integrins and altered extracellular matrix components connecting to these integrins, leading to an exacerbated fibrotic response during pathological remodelling. CONCLUSION: Sorbs2 is a cardiomyocyte-enriched gene that is increased during progression to heart failure in a GATA4-dependent manner and correlates to phenotypical hallmarks of cardiac failure. Our data indicate SORBS2 to function as a crucial regulator of integrin interactions and cardiac fibrosis.