FRZB Attenuates Ferroptosis and Oxidative Stress in Diabetic Cardiomyopathy by Modulating the AMPK/PGC-1α Signaling Pathway: A Novel Cardioprotective Mechanism

Background: Diabetic Cardiomyopathy (DCM), a common cardiac complication in diabetic patients, is characterized by cardiac structural injury and myocardial metabolic dysfunction, ultimately leading to heart failure. Frizzled Related Protein (FRZB) contributes to the regulation of a variety of diseases, including diabetes and cardiovascular failure. However, the specific mechanism underlying its role in DCM is unclear. Therefore, this study investigated the cardioprotective role of FRZB in diabetic heart injury. Methods: Male C57BL/6J mice were employed to construct an <i>in vivo</i> DCM mouse model using a high-fat diet combined with a streptozotocin injection. Similarly, an <i>in vitro</i> DCM model was established in H9C2 cells through high glucose (HG) exposure. Histological staining, Cell Counting Kit-8 assay, TdT-mediated dUTP Nick-End Labeling (TUNEL staining), flow cytometry, and biochemical kits were used to examine cardiac tissue morphology, cell activity, apoptosis and oxidative stress. The expression levels of ferroptosis-related indicators were quantified. Furthermore, FRZB was overexpressed or knocked down to assess its effect and determine changes in Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)/Peroxisome proliferator-activated receptor-γ-coactivator 1α (PGC-1α) signaling pathway-related protein levels after HG exposure. Results: HG induced cardiomyocyte injury, ferroptosis and oxidative stress, along with downregulation of FRZB expression <i>in vitro</i> and <i>in vivo</i>. Overexpression of FRZB activated the AMPK/PGC-1α signaling pathway and significantly attenuated HG-induced oxidative stress and ferroptosis in cardiomyocytes. In contrast, silencing of FRZB effectively inhibited this pathway, exacerbating oxidative stress and ferroptosis under HG conditions. Additionally, when FRZB was overexpressed while inhibiting the AMPK/PGC-1α signaling pathway, its cardioprotective effects were abolished. Conclusion: FRZB attenuates diabetes-induced oxidative stress and ferroptosis in cardiomyocytes by regulating the AMPK/PGC-1α signaling pathway, offering novel insights into the cardioprotective mechanisms for diabetic patients.