AJUBA Attenuates Pathological Cardiac Hypertrophy by Enhancing NEDD4‐Mediated Ubiquitination and Degradation of DVL2

ABSTRACT Cardiac hypertrophy, a response to pathological stimuli, eventually progresses to heart failure (HF). AJUBA is a multifunctional protein expressed in various human tissues, serving as a critical modulator of cellular processes and signalling pathways involved in cardiac hypertrophy and remodelling. It plays significant roles in cellular signalling, gene transcription, and cytoskeletal organisation, modulating cardiac growth, inflammation, and cell survival. However, the precise function of AJUBA in cardiac hypertrophy remains unclear. In the present study, we examined its function as a novel regulator of HF and pathological cardiac hypertrophy. AJUBA expression was significantly decreased in patients with HF and in mouse models subjected to pressure overload. Using AJUBA knockout mice, we found that compromised echocardiographic function and increased heart weight‐to‐body weight ratios are signs of worsened cardiac hypertrophy and dysfunction due to AJUBA deficiency. Mechanistic studies revealed that AJUBA acts as a co‐activator of C/EBPβ, enhancing the transcription of NEDD4, which promotes the ubiquitin‐mediated degradation of DVL2. This prevents the activation of the Ca 2+ /calmodulin‐dependent protein kinase II/histone deacetylase 4 signalling pathway, which is essential for heart hypertrophy. Furthermore, during in vitro experiments, AJUBA overexpression reduced hypertrophic responses in cardiomyocytes, whereas AJUBA silencing intensified these changes. Therefore, these findings underscore the protective role of AJUBA in maintaining cardiac homeostasis. Targeting AJUBA or its associated pathways may offer viable therapeutic strategies for regulating HF and cardiac hypertrophy.