FTO deficiency facilitates epithelia dysfunction in oral lichen planus
Yufeng Fan1,2, Yukai Hao1,2, Yan Ding3,4
1Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China.
Molecular Therapy. Nucleic Acids
|February 25, 2025
Summary
Fat mass and obesity-associated protein (FTO) deficiency worsens oral lichen planus (OLP) by reducing Vitamin D receptor (VDR) expression, leading to epithelial dysfunction and increased apoptosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Oral Pathology
Background:
- The fat mass and obesity-associated protein (FTO) is a key RNA demethylase involved in various cellular processes.
- The specific role of FTO in oral lichen planus (OLP), an inflammatory oral mucosal disease, is currently unknown.
- Understanding FTO's function in OLP could reveal novel therapeutic targets.
Purpose of the Study:
- To investigate the role and molecular mechanisms of FTO in oral lichen planus (OLP).
- To determine the relationship between FTO, Vitamin D receptor (VDR), and epithelial dysfunction in OLP.
- To elucidate how FTO impacts inflammatory and apoptotic pathways in oral keratinocytes.
Main Methods:
- Quantitative analysis of FTO protein levels in oral keratinocytes from OLP patients and healthy controls.
- Investigation of FTO protein degradation pathways, including the role of GSK-3β-induced phosphorylation.
- Utilizing a cell co-culture model to assess the effects of FTO deficiency on NF-κB activation and apoptosis.
- Examining the interplay between FTO, VDR expression, and RNA N6-methyladenosine (m6A) methylation.
- Employing VDR ablation in oral keratinocytes to validate FTO's mechanism of action.
Main Results:
- FTO protein levels were significantly down-regulated in oral keratinocytes from OLP patients compared to healthy controls.
- GSK-3β-induced phosphorylation was identified as a mechanism promoting FTO protein degradation in diseased oral keratinocytes.
- FTO deficiency exacerbated NF-κB activation and apoptosis in oral keratinocytes under inflammatory conditions.
- FTO mediated Vitamin D receptor (VDR) expression in an RNA m6A methylation-dependent manner.
- FTO overexpression could not rescue NF-κB and caspase-3 activation upon VDR ablation, indicating VDR is a key target.
Conclusions:
- FTO deficiency contributes to epithelial dysfunction in oral lichen planus (OLP) by down-regulating Vitamin D receptor (VDR) expression.
- The GSK-3β/phosphorylation pathway promotes FTO degradation, exacerbating OLP pathogenesis.
- Targeting FTO or restoring VDR levels may represent a therapeutic strategy for OLP.
