Adipocyte Enhancer Binding Protein 1 (AEBP1) Inhibition as a Potential Anti-Fibrotic Therapy in Heart Failure

Persistent activation of cardiac fibroblasts into myofibroblasts drives excessive extracellular matrix deposition, leading to maladaptive myocardial fibrosis, adverse remodeling and heart failure (HF) progression. Adipocyte enhancer binding protein 1 (AEBP1) and Aortic carboxypeptidase-like protein (ACLP, full-length AEBP1 protein coded by AEBP1) has been implicated in pathological fibrosis across multiple organs, with tissue-specific knockdown attenuating fibrosis in preclinical models. Although elevated AEBP1 expression has been associated with human HF, its role in myocardial fibrosis progression in vivo remains undefined. Here, we demonstrated that AEBP1 is a critical mediator of myocardial fibrosis and adverse cardiac remodeling. Fibroblast-specific knockout and cardiac-specific knockdown of Aebp1 significantly improved cardiac function and prevented pathological remodeling in murine models of myocardial ischemia and pressure-overload induced injury. In ex vivo human myocardial tissue culture studies, ACLP overexpression in non-failing hearts induced pathological remodeling, whereas AEBP1 knockdown in failing human hearts induced structural reverse remodeling. Mechanistically, we also showed that ACLP regulates key pro-fibrotic transcription factors and genes, including MRTFB, RUNX2, SM22 and COL1A1, thereby orchestrating fibroblast activation. Collectively, these findings establish AEBP1 as a central driver of myocardial fibrosis and highlights its inhibition as a promising therapeutic strategy to mitigate both acute and chronic HF.