Related Experiment Video
Updated: Jun 11, 2025
Author Spotlight: Unraveling the Molecular Mechanisms in PCO and Fibrosis Following Cataract Surgery
Published on: December 1, 2023
METTL3-mediated m6A modification of SIRT1 mRNA affects the progression of diabetic cataracts through cellular
Su Dong1, Jiajia Zhang1, Yushan Fu1
1Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
Background:
The increasing incidence of diabetes mellitus has established diabetic cataracts (DC) as a significant worldwide public health issue. The mechanisms underlying DC remain unknown, and effective prevention and treatment strategies are lacking. Accordingly, we aimed to explore the role and mechanism behind N6-methyladenosine (m6A) in DC progression.
Methods:
Methyltransferase-like 3 (METTL3), p21, Beclin1, LC3, and p62 expression levels were measured in human tissues. This study assessed total m6A levels and common m6A-regulated biomarkers in both in vitro and in vivo DC models. Autophagy flux was detected in vitro through Ad-mCherry-GFP-LC3B and Monodansylcadaverine (MDC) staining. Cellular senescence was assessed utilizing the senescence-associated β-galactosidase (SA-β-Gal) assay. Furthermore, the effect of METTL3 on SIRT1 mRNA modification was demonstrated, and its mechanism was elucidated using RT-qPCR, western blot, RNA stability assays, and RIP analysis.
Results:
METTL3, p21, and p62 expression levels were elevated in lens epithelial cells (LECs) from DC patients, while Beclin1 and LC3 levels were reduced. Silencing METTL3-mediated m6A modifications restored high-glucose-induced autophagy inhibition and prevented premature senescence in LECs. Notably, SIRT1720 and Metformin significantly enhanced autophagosome generation and delayed cellular senescence. The m6A-reading protein YTHDF2 bound to m6A modifications, and YTHDF2 silencing significantly reduced METTL3-mediated SIRT1 inactivation.
Conclusions:
METTL3 induces senescence in DC by destabilizing SIRT1 mRNA in an m6A-YTHDF2-dependent manner. The METTL3-YTHDF2-SIRT1 axis is a key target and potential pathogenic mechanism in DC.
Insights
N6-methyladenosine (m6A) modification, driven by METTL3, promotes diabetic cataract (DC) progression by destabilizing SIRT1 mRNA. Targeting the METTL3-YTHDF2-SIRT1 pathway offers a potential strategy for DC prevention and treatment.
Area of Science:
- Molecular Biology
- Epigenetics
- Ophthalmology
Background:
- Diabetic cataracts (DC) are a growing global health concern due to rising diabetes mellitus incidence.
- Current understanding of DC pathogenesis is limited, hindering effective prevention and treatment strategies.
Purpose of the Study:
- To investigate the role and mechanism of N6-methyladenosine (m6A) in the progression of diabetic cataracts.
- To explore potential therapeutic targets within the m6A regulatory pathway for DC.
Main Methods:
- Assessed expression of METTL3, p21, Beclin1, LC3, and p62 in human DC tissues.
- Utilized in vitro and in vivo DC models to evaluate m6A levels and biomarkers.
- Analyzed autophagy flux, cellular senescence, and METTL3's effect on SIRT1 mRNA using molecular biology techniques.
Main Results:
- Elevated METTL3, p21, and p62, with reduced Beclin1 and LC3, were observed in DC patient lens epithelial cells (LECs).
- METTL3 inhibition reversed high-glucose-induced autophagy suppression and prevented premature senescence in LECs.
- The METTL3-YTHDF2 interaction was crucial for SIRT1 mRNA destabilization and inactivation, contributing to DC pathogenesis.
Conclusions:
- METTL3 promotes cellular senescence in diabetic cataracts by destabilizing SIRT1 mRNA via an m6A-YTHDF2-dependent mechanism.
- The METTL3-YTHDF2-SIRT1 axis represents a key pathogenic pathway and a potential therapeutic target for diabetic cataracts.
More Related Videos
14:32Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
Published on: February 27, 2016
05:58Mouse Electroacupuncture Fixation Device Fabrication for Electroacupuncture Pretreatment in Diabetic Cardiomyopathy Mouse Model
Published on: April 18, 2025
