Overall, our study elucidated that downregulation of SFRP4 attenuated cardiomyocyte injury in H/R models and regulated the activation of the P13 K/AKT signaling pathway through PTPN12, which possibly provides a novel therapeutic target for patients with diabetic cardiomyopathy. The gene discussed is SFRP4; the disease is diabetic cardiomyopathy.