SAP30BP aggravates mitochondrial-related ferroptosis in diabetic cardiomyopathy by regulating MFN2-ACSL4 axis.

Abstract

Ferroptosis is characterized by iron overload and uncontrolled lipid peroxidation, which plays a substantial role in the development of diabetic cardiomyopathy (DCM). However, the exact factor responsible for inducing ferroptosis in DCM has not been fully elucidated. SAP30 binding protein (SAP30BP), a member of the HCNGP family, functions as a transcription regulator. Our research reveals a significant increase in SAP30BP expression in the hearts of DCM mice and cardiomyocytes treated with high glucose (HG). Knockdown of SAP30BP ameliorated cardiac dysfunction and inhibited ferroptosis and mitochondrial damage in DCM hearts. At the cellular levels, transfection of si-SAP30BP suppressed ferroptosis, as evidenced by the reduced oxidative stress, iron overload and lipid peroxidation. RNA-seq and GEO database analysis suggested that mitochondrial dynamics contributed to SAP30BP induced ferroptosis. Mechanistically, SAP30BP inhibited the transcription of MFN2 through HDAC1-mediated histone deacetylation, leading to mitochondrial dynamic disruption and dysfunction. This process ultimately hindered the mitochondrial translocation of ACSL4 and mitochondria-associated ferroptosis. Collectively, our findings demonstrate the therapeutic benefits of SAP30BP knockdown in DCM by effectively suppressing mitochondria-associated ferroptosis through the MFN2-ACSL4 pathway. These results provide new mechanistic insights and a basis for developing mitochondria and ferroptosis targeting therapies for DCM.