HIPK2 Contributes to Diabetic Cardiomyocyte Injury Through Elevating Phosphorylated Tp53

Diabetic cardiomyopathy (DCM) is a major cardiovascular complication of diabetes, characterized by progressive cardiac dysfunction and cardiomyocyte apoptosis, in which high glucose (HG)-induced apoptosis plays a central role. Homeodomain-interacting protein kinase 2 (HIPK2), a conserved nuclear kinase, regulates critical processes including cell apoptosis, proliferation, and stress response. However, its specific role in cardiomyocyte apoptosis under diabetic conditions remains unclear. In this study, we established an in vivo DCM mouse model and an in vitro HG-induced injury model using AC16 human cardiomyocytes. We found that HIPK2 expression was significantly upregulated in both cardiac tissues of DCM mice and HG-treated AC16 cells. Pharmacological inhibition of HIPK2 with protein kinase inhibitor 1 hydrochloride (PKI1H) or genetic knockdown using si-HIPK2 significantly ameliorated HG-induced cardiomyocyte apoptosis. Mechanistically, HIPK2 promoted cardiomyocyte apoptosis in association with increased phosphorylation of Tp53 at serine 15 (p-Tp53 Ser15 ). These findings indicate that HIPK2 promotes DCM-associated cardiomyocyte apoptosis through a Tp53-dependent pathway and suggest that HIPK2 inhibition may represent a potential proof-of-concept strategy for mitigating diabetes-induced cardiac dysfunction. Further preclinical studies are required to evaluate its therapeutic efficacy and safety.