Targeting CREB1 in cardiac diseases therapy

Cyclic AMP-responsive element-binding protein 1 (CREB1) family is integral to the regulation of gene expression in response to diverse cellular signals, functioning as both an activator and a repressor depending on the cellular contest. The activity of CREB1 is tightly regulated by phosphorylation, alternative splicing, and co-activator interactions, enabling it to integrate multiple signaling pathways and precisely control processes. In the cardiac diseases, CREB1 emerges as a critical regulator. Evidence indicates that CREB1 upregulation reduces cardiomyocyte apoptosis and enhances cardiac function post-infarction. At the same time, its downregulation is linked to impaired contractility and dilated cardiomyopathy, highlighting its role as both a protective factor in cardiac pathology. This review examines the central CREB1-related signaling cascades, such as the CREB1/the homeodomain-interacting protein kinase 3 (HIPK3)/microRNA-17-3p/the adenylate cyclase type 6 (ADCY6) and CREB1- the bone morphogenetic proteins 10 (BMP10)-Smad1/5/8 axes, delineating their upstream activators and downstream targets in cardiac disease. Collectively, these findings underscore the therapeutic potential of targeting CREB1 and its regulatory networks for the management of diverse cardiac conditions.