Targeting EPAC1 to treat iron-induced heart failure
Description: The heart is one of the main organs affected by excess iron accumulation, and thus iron-loading conditions are primarily manifested as cardiac dysfunction and failure. Cardiac iron overload is also frequent in disorders of iron homeostasis such as hemochromatosis (the most prevalent genetic disease in France) and thalassemia. Interestingly, ferroptosis a novel type of iron-dependent cell death that is caused by lipid peroxidation and fueled by excessive intracellular iron accumulation. It is a major driver of cardiomyocyte death in many cardiac diseases. These observations indicate that iron overload and ferroptosis play a crucial role in cardiomyocyte death and pathological cardiac remodeling leading to HF. However, the mechanisms involved in the regulation of iron metabolism and ferroptosis in the cardiomyocyte are still poorly understood. Our strong preliminary data show that ablation of the cyclic AMP-binding protein EPAC1 in mice prevents anthracycline-induced cardiac iron overload and peroxidation suggesting that EPAC1 regulates cardiac iron transport and metabolism and ferroptosis in stress conditions. Our main research hypotheses are: i) EPAC1 deregulates iron metabolism and promotes ferroptosis during pathological cardiac stress-induced heart failure (HF); ii) Blocking EPAC1 activity decreases cardiac ferroptosis and HF development associated with iron excess. Therefore, the general objective of the present project is dual: to investigate the links between activation of cAMP signaling pathways, iron metabolism and ferroptosis in heart failure (WP1, WP2, WP4) and to determine whether targeting EPAC1 can protect from iron overload, cardiomyocyte ferroptosis and HF in murine models of iron overload (WP3). This project will elaborate on novel insights into how dysregulation of iron metabolism contributes to cell injury in cardiac disease. The ambition is to demonstrate that targeting an unsuspected regulatory mechanism of iron metabolism prevents HF progression
Funder: Agence Nationale de la Recherche
Amount: €520,900
Funding type: research
Funder scheme: AAPG2025
Start date: 2026-01-01
Investigator: Frank LEZOUALC'H
Institution: Institut des maladies métaboliques et cardiovasculaires
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Funded outputs count: 1
Funder award ID: ANR-25-CE14-1682
OpenAlex ID: G7006341887