Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects

TL;DR: The current study aimed to identify the key molecules involved in β-cell ferroptosis3 in patients with T2D using the mRNA expression profile data of GSE25724 by bioinformatic approaches and constructed a regulatory network of hub genes and miRNAs, and the results showed that hsa-miR-6855-5p, hsa

TL;DR: In future clinical trials involving subjects with MASLD (especially with the intervention of the therapeutic drugs), the detection of serum iron metabolism levels and ferroptosis markers in patients should be increased to further explore the efficacy of potential drugs on ferroPTosis.

Abstract: Abstract 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 Fe 2 ⁺, 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.

Abstract: Additional file 1. The Supplementary methods: including section 1 to section 7.

TL;DR: Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity.

TL;DR: It is shown that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non-apoptotic form of cell death, by repressing expression of SLC7A11, a key component of the Cystine/glutamate antiporter.

TL;DR: This review will provide a brief overview of lipid peroxidation, as well as key components involved in the ferroptotic cascade, focusing on established NRF2 target genes that mitigate these pathways, and the relevance of theNRF2-lipid per oxidation-ferroptosis axis in disease.

TL;DR: It is reported that inhibition of ferritinophagy by blockage of autophagy or knockdown of NCOA4 abrogated the accumulation of ferroptosis-associated cellular labile iron and reactive oxygen species, as well as eventual ferroPTotic cell death.