Crosstalk between ferroptosis and miRNA in type 2 diabetes mellitus and possible therapeutic targeting.

Type 2 diabetes (T2D) accounts for over 90% of diabetes mellitus and is characterized by peripheral tissue insulin resistance, a defective compensatory insulin secretion, and reduced insulin output from pancreatic β-cells. T2D is a complex metabolic syndrome involving multiple cell types within multiple organs, such as the liver, muscle, adipose tissue, and pancreas. Because the adult human endocrine pancreas does not have regenerative capability, understanding of the pathogenesis of T2D is vital for working out successful strategies for the delay or arrest of disease development. Newly, ferroptosis, an iron-dependent, regulated cell death, has emerged as a significant promoter of the pathogenesis and development of T2D. Ferroptosis is distinguishable from apoptosis, autophagy, and necroptosis, and is characterized by the accumulation of iron, lipid peroxidation, and suppression of glutathione peroxidase 4 (GPX4). Ferroptosis in pancreatic β-cells results in the defective secretion of insulin. The labile iron pool (LIP), particularly Fe2⁺, enhances the formation of reactive oxygen species (ROS) during the Fenton reaction, thereby leading to ferroptosis. Recent empirical studies have revealed an exquisite regulatory interaction between ferroptosis and microRNAs (miRNAs), with the implication being that miRNAs play a central role in the regulation of ferroptosis during T2D. Two-way regulation of ferroptosis by miRNAs has been highlighted herein, with special focus on new insights and the speculation on the potential of using inhibition of ferroptosis as a strategy for treatment. Therapeutic approaches targeting ferroptosis include the use of ferroptosis inhibitors, such as Ferrostatin-1 and Deferoxamine, and miRNA-guided therapy that regulates iron homeostasis and lipid peroxidation. Such interventions may find practical applications in sustaining β-cell function and stimulating insulin secretion in diabetic patients. In conclusion, understanding the molecular mechanisms that regulate ferroptosis and identifying specific drugs targeting ferroptosis and associated miRNAs may unlock novel and effective therapies for individuals with T2D.