Diabetes is well recognized to increase the risk of heart failure, which is associated with higher mortality and morbidity. It is important for the development of novel therapeutic methods targeting heart failure in diabetic patients. Ferroptosis, an iron-dependent regulated cell death, has been implicated in the progression of diabetes-induced heart failure (DIHF). This study was designed to investigate the contribution of Nr2f2 to the activation of ferroptosis and mitochondrial dysfunction in DIHF. We established a diabetic model by a high-fat feeding diet combined with an intraperitoneal injection of streptozotocin. After 16 weeks, Nr2f2 expression was increased in heart tissue of DIHF mice. In vivo, DIHF mice overexpressing Nr2f2 (AAV9-cTNT-Nr2f2) exhibited severe heart failure and enhanced cardiac ferroptosis compared with DIHF control mice (AAV9-cTNT-ctrl), accompanied by mitochondrial dysfunction and aggravated oxidative stress reaction. In vitro, Nr2f2 knockdown ameliorated ferroptosis and mitochondrial dysfunction by negatively regulating PGC-1α, a crucial metabolic regulator. PGC-1α knockdown counteracted the protective effect of Nr2f2 knockdown. These data suggest that Nr2f2 promotes heart failure and ferroptosis in DIHF by modulating the PGC-1α signaling. Our study provides a new idea for the treatment of diabetes-induced heart failure.

Diabetes is a complex metabolic disease. In recent years, diabetes and its chronic complications have become a health hotspot of global concern. It is very important to find promising therapeutic targets and directions. Ferroptosis is a new type of programmed cell death that is different from cell necrosis, apoptosis and autophagy. Ferroptosis is mainly characterized by iron-dependent lipid peroxidation. With the reduction of the anti-oxidative capacity of cells, the accumulated reactive lipid oxygen species will cause oxidative cell death and lead to ferroptosis at lethal levels. Recent studies have shown that ferroptosis plays an important regulatory role in the initiation and development of diabetes, as well as various complications of diabetes. In this review, we will summarize new findings related to ferroptosis and diabetic complications, and propose ferroptosis as a potential target for treating diabetic complications.

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