Conclusions
The PACS2/CPT1A/DHODH signalling pathway may be involved in ferroptosis in DCM by regulating cardiomyocyte mitochondrial function.
Results
Cardiomyocytes were treated with high glucose and palmitic acid (HGPA), and the detection of cardiomyocyte iron ions, lipid peroxides, and reactive oxygen species (ROS) revealed clear ferroptosis during these treatments. Silencing PACS2 downregulated CPT1A expression and upregulated DHODH expression significantly, reversing HGPA-induced ferroptosis. Further silencing of PACS2 with a CPT1A agonist exacerbated cardiomyocyte ferroptosis while promoting mitochondrial damage in cardiomyocytes. Using a mouse model of type 2 diabetes induced by streptozotocin (STZ) and a high-fat diet (HFD), we found that PACS2 deletion reversed these treatment-induced increases in cellular iron ions, impaired cardiac function, mitochondrial damage and ferroptosis in cardiac muscle tissues. Conclusions: The PACS2/CPT1A/DHODH signalling pathway may be involved in ferroptosis in DCM by regulating cardiomyocyte mitochondrial function.