Farrerol and the miR-29b-3p/sirtuin 1 pathway: A mechanistic breakthrough in protecting the diabetic heart

Abstract

Diabetic cardiomyopathy (DCM) is a cardiac muscle disorder that causes heart failure independently of coronary artery disease. This condition remains a major clinical challenge, as current therapies primarily address traditional risk factors rather than the underlying molecular pathology. In this regard, endothelial dysfunction in the cardiac microvasculature is a key factor in DCM, linking metabolic alterations to impaired myocardial perfusion and fibrosis. Ferroptosis is a unique form of iron-dependent, regulated cell death characterized by lipid peroxidation. This mechanism has been linked to various diabetic complications, although its role in chronic diabetic heart disease remains unclear. In this editorial, we discuss new evidence highlighting endothelial cell ferroptosis as a key mechanism in DCM and a promising therapeutic target. Specifically, we discuss the recent study by Guo et al, demonstrating that farrerol, a natural flavonoid, improves DCM in mice by inhibiting endothelial ferroptosis through the microRNA-29b-3p/sirtuin 1 signaling axis. The findings of Guo et al reveal that downregulation of microRNA-29b-3p by farrerol is able to restore sirtuin 1 levels in cardiac endothelial cells, activating antioxidant defenses and preventing ferroptotic injury. Importantly, the endothelial protection generated by Farrerol translated into improvements in cardiac function and a reduction in fibrosis in diabetic mice. These results open a new therapeutic opportunity for the treatment of DCM by targeting the cardiac microvascular endothelium. Future studies should build on this mechanistic knowledge, addressing the challenges of converting Farrerol, a natural compound with antioxidant and antiferroptotic properties, or other ferroptosis inhibitors into targeted therapies that safely benefit patients with diabetic heart disease.

Keywords: Diabetic cardiomyopathy; Endothelial dysfunction; Ferroptosis; MicroRNA-29b-3p; Sirtuin 1; Farrerol

Core Tip: Diabetic cardiomyopathy (DCM) is a diabetes-related form of heart failure that lacks targeted therapies. Recent evidence identifies endothelial ferroptosis, an iron-dependent form of cell death, as a central driver of cardiac microvascular injury in DCM. Guo et al demonstrate that Farrerol, a natural flavonoid, inhibits ferroptosis by downregulating microRNA-29b-3p and restoring sirtuin 1 signaling in endothelial cells, thereby improving cardiac function and reducing fibrosis in diabetic mice. Targeting endothelial ferroptosis through the microRNA-29b-3p/sirtuin 1 pathway represents a novel disease-modifying strategy for DCM.