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

• • CDC5L overexpression significantly increased cardiomyocyte proliferation markers: Ki67+ (cell cycle re-entry), EdU+ (DNA synthesis), and pH3+ (mitosis) in OGD/R models, with concurrent reduction in TUNEL+ apoptotic cells and Bax/Bcl-2 ratio, indicating a dual pro-proliferative and anti-apoptotic effect. This dual mechanism is critical because adult cardiomyocytes are terminally differentiated; reactivating the cell cycle while suppressing apoptosis could achieve meaningful myocardial regeneration, a feat not accomplished by current reperfusion therapies. • • FGF10 knockdown completely reversed CDC5L-mediated proliferative and anti-apoptotic effects, and abolished the reduction in YAP phosphorylation. This establishes FGF10 as an obligatory downstream effector and YAP as a downstream target of FGF10. The dependence on FGF10 implies that therapeutic strategies must ensure sustained FGF10 availability; direct CDC5L activation alone would be insufficient if FGF10 is suppressed in the ischemic milieu. • • In vivo, CDC5L overexpression via AAV9 preserved cardiac function (echocardiography) and reduced infarct size in adult mice subjected to I/R injury. These functional improvements occurred alongside increased FGF10 and cyclin D1 expression and decreased phosphorylated YAP. The in vivo efficacy in adult mice, which have limited regenerative capacity, suggests translational potential, though dosing, delivery efficiency, and long-term safety of AAV9-CDC5L remain to be optimized. • • CDC5L overexpression did not affect γ-H2AX expression, a DNA damage marker, indicating that its protective effects are not mediated through DNA damage repair. This specificity narrows the mechanism to proliferation and apoptosis modulation, reducing the likelihood of off-target effects on genomic stability. Clinically, this implies that CDC5L-based therapies would not interfere with DNA repair pathways, potentially lowering oncogenic risks associated with uncontrolled proliferation.