Experimental and molecular pathologyMay 17, 2025

m6A demethylases FTO and ALKBH5 may worsen diabetes-related blood vessel cell problems by lowering lncRNA H19 levels

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 22, 2026

Abstract

m6A levels were decreased in diabetic patients and a diabetic mouse model, while demethylases FTO and ALKBH5 were upregulated.

High glucose exposure led to reduced m6A levels and increased expression of the demethylases FTO and ALKBH5 in human endothelial cells.
Silencing FTO and ALKBH5 restored m6A levels and alleviated dysfunction in human umbilical vein endothelial cells (HUVECs) subjected to high glucose.
Differentially expressed long non-coding RNAs (lncRNAs), including H19, were identified in HUVECs under high glucose conditions.
FTO and ALKBH5 inhibited H19 expression by decreasing m6A modification in H19 transcripts.
The FTO/ALKBH5/H19 pathway was implicated in high glucose-induced dysfunction of HUVECs.
Silencing H19 promoted the expression of cell cycle-related genes by interacting with EZH2 and affecting histone modification.

Simplified

Endothelial cell dysfunction induced by glucose is the most important cause of diabetic vascular complications, which are the leading causes of blindness, disability, renal failure, heart failure, stroke, and even death in diabetic patients. RNA m6A modification is involved in the pathogenesis of human disease. However, the role and underlying mechanism of RNA m6A modification in high glucose-induced endothelial cell dysfunction is not well understood. Herein, this study first demonstrated that m6A levels were decreased and that the demethylases FTO and ALKBH5 were upregulated in diabetic patients and an STZ-induced diabetic mouse model. This study revealed that high glucose induced decreased m6A levels and increased expression of FTO and ALKBH5, and silencing of FTO and ALKBH5 restored high glucose-induced decreases in m6A levels and dysfunction of HUVECs. Next, this study systematically screened differentially expressed lncRNAs, including H19, in HUVECs under high glucose conditions. This study revealed that FTO-ALKBH5 inhibited H19 expression by decreasing m6A modification in H19 transcripts. In addition, this study demonstrated the role of the FTO/ALKBH5/H19 pathway in high glucose-induced cellular dysfunction of HUVECs. Ultimately, this study uncovered that silencing of H19 promoted the expression of cell cycle-related genes, including PTEN, p21 and p27 via interacting with EZH2 and affecting the H3K27me3 histone modification. Overall, this study is the first to dissect the regulation of lncRNA by m6A modification in hyperglycaemia, identifying a new regulatory pathway in high glucose-induced cellular dysfunction and providing biomarkers with the potential to serve as therapeutic targets for high glucose-induced cellular dysfunction.

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Declaration of competing interest The authors declare no potential conflicts of interest.

PubMed

m6A demethylases FTO and ALKBH5 may worsen diabetes-related blood vessel cell problems by lowering lncRNA H19 levels

Abstract

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Abstract

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