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The RNA Demethyltransferase FTO Regulates Ferroptosis in Major Depressive Disorder
Kexin Meng1,2, Zijing Liu1,2, Yuesong Yu1,2
1State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
Abstract:
Major depressive disorder (MDD) is a widespread and severe mental health condition characterized by persistent low mood and loss of interest. Emerging evidence suggests that ferroptosis, an iron-dependent form of cell death, and epigenetic dysregulation contribute to the pathogenesis of MDD. This study investigates the role of RNA demethylase FTO and autophagy regulator BECN1 in ferroptosis and their regulation by the active compound ginsenoside Rb1 (GRb1) as a potential antidepressant strategy. Hippocampal tissues from postmortem MDD patient brains and mice with chronic restraint stress (CRS)-induced depression were analyzed. Ferroptosis was evaluated by analyzing the levels of markers such as glutathione (GSH) and malondialdehyde (MDA). GRb1 was administered to CRS model mice by gavage to explore its effects on ferroptosis-related pathways. The results showed that FTO and BECN1 expression was reduced in the hippocampal tissues of MDD patients and CRS model mice, promoting ferroptosis via disruption of the antioxidant system. Moreover, GRb1 treatment increased FTO and BECN1 expression, modulated m6A methylation, restored the antioxidant balance, and inhibited ferroptosis in CRS model mice. These findings reveal a novel epigenetic mechanism of ferroptosis in MDD and highlight GRb1 as a promising agent for treating depression through the targeting of ferroptosis pathways.
Insights
Major depressive disorder (MDD) involves ferroptosis and epigenetic changes. Ginsenoside Rb1 (GRb1) shows promise for depression by regulating FTO, BECN1, and ferroptosis pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Major depressive disorder (MDD) is a prevalent mental health condition linked to ferroptosis and epigenetic dysregulation.
- Ferroptosis, an iron-dependent cell death, and epigenetic factors are increasingly implicated in MDD pathogenesis.
Purpose of the Study:
- To investigate the roles of RNA demethylase FTO and autophagy regulator BECN1 in ferroptosis within MDD.
- To explore the potential of ginsenoside Rb1 (GRb1) in modulating these pathways as an antidepressant strategy.
Main Methods:
- Analysis of hippocampal tissues from postmortem MDD patients and a mouse model of chronic restraint stress (CRS).
- Assessment of ferroptosis markers (GSH, MDA) and expression levels of FTO and BECN1.
- Administration of GRb1 to CRS mice to evaluate effects on m6A methylation, antioxidant balance, and ferroptosis.
Main Results:
- Reduced FTO and BECN1 expression were observed in MDD patients and CRS mice, correlating with increased ferroptosis.
- GRb1 treatment upregulated FTO and BECN1, normalized m6A methylation, and restored antioxidant balance in CRS mice.
- GRb1 effectively inhibited ferroptosis in the depression model.
Conclusions:
- A novel epigenetic mechanism involving FTO, BECN1, and ferroptosis is identified in MDD.
- Ginsenoside Rb1 demonstrates potential as a therapeutic agent for depression by targeting ferroptosis pathways.
