CDC5L facilitates cardiomyocyte proliferation and ameliorates myocardial ischemia-reperfusion injury via modulation of the FGF10-YAP axis

Myocardial infarction (MI) causes irreversible cardiomyocyte loss, creating a need for cardiac repair therapies. The role of cell division cycle 5-like (CDC5L), a cell cycle regulator, in cardiac repair is unknown. This study aims to define the role of CDC5L in mitigating ischemia-reperfusion (I/R) injury by assessing its impact on cardiomyocyte proliferation and apoptosis and to determine the mechanism involving the FGF10-YAP axis. We model cardiac injury using <i>in vitro</i> oxygen-glucose deprivation/reoxygenation (OGD/R) in neonatal mouse cardiomyocytes and <i>in vivo</i> I/R in adult mice. To investigate CDC5L function, we modulate its expression via adenoviral or AAV9-mediated overexpression or knockdown. Proliferation markers (EdU ⁺, Ki67 ⁺, pH3 ⁺), apoptosis (TUNEL staining, Bax/Bcl-2 ratio), and cardiac function (echocardiography) are assessed. Through transcriptomic screening, we identify CDC5L downstream targets and validate their functional roles using <i>FGF10</i> knockdown rescue assays. We find that CDC5L is upregulated in the post-I/R murine myocardium. Its overexpression enhances cardiomyocyte proliferation, preserves cardiac function, reduces apoptosis, and diminishes infarct size. Transcriptomic analysis identifies FGF10 as a key downstream effector, and we confirm that CDC5L upregulates FGF10 expression. Notably, <i>FGF10</i> knockdown reverses the proliferative and anti-apoptotic effects of CDC5L. Moreover, the CDC5L-mediated reduction in YAP phosphorylation is also dependent on FGF10, as this effect is abolished upon <i>FGF10</i> knockdown. In conclusion, CDC5L attenuates cardiac I/R injury by promoting cardiomyocyte proliferation and inhibiting apoptosis through the FGF10-YAP pathway. This CDC5L-FGF10-YAP axis represents a promising therapeutic target to improve myocardial regeneration and recovery after myocardial infarction.