Fto-dependent Vdac3 m6A Modification Regulates Neuronal Ferroptosis Induced by the Post-ICH Mass Effect and Transferrin.
10.1007/s12264-025-01355-x
- Author:
Zhongmou XU
1
;
Haiying LI
1
;
Xiang LI
1
;
Jinxin LU
2
,
3
;
Chang CAO
1
;
Lu PENG
1
;
Lianxin LI
1
;
John ZHANG
4
;
Gang CHEN
3
,
5
Author Information
1. Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China.
2. Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China. ljx54257@
3. com.
4. Departments of Neurosurgery, Anesthesiology, Physiology and Pharmacology, Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.
5. Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China. nju_neurosurgery@
- Publication Type:Journal Article
- Keywords:
Ferroptosis;
Intracerebral hemorrhage;
M6A methylation;
Mass effect;
Transferrin;
Vdac3
- MeSH:
Ferroptosis/physiology*;
Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics*;
Animals;
Neurons/metabolism*;
Transferrin/pharmacology*;
Mice;
Methylation;
Mice, Inbred C57BL;
Adenosine/metabolism*;
RNA, Messenger/metabolism*;
Male;
Oxidative Stress/physiology*
- From:
Neuroscience Bulletin
2025;41(6):970-986
- CountryChina
- Language:English
-
Abstract:
During the hyperacute phase of intracerebral hemorrhage (ICH), the mass effect and blood components mechanically lead to brain damage and neurotoxicity. Our findings revealed that the mass effect and transferrin precipitate neuronal oxidative stress and iron uptake, culminating in ferroptosis in neurons. M6A (N6-methyladenosine) modification, the most prevalent mRNA modification, plays a critical role in various cell death pathways. The Fto (fat mass and obesity-associated protein) demethylase has been implicated in numerous signaling pathways of neurological diseases by modulating m6A mRNA levels. Regulation of Fto protein levels in neurons effectively mitigated mass effect-induced neuronal ferroptosis. Applying nanopore direct RNA sequencing, we identified voltage-dependent anion channel 3 (Vdac3) as a potential target associated with ferroptosis. Fto influenced neuronal ferroptosis by regulating the m6A methylation of Vdac3 mRNA. These findings elucidate the intricate interplay between Fto, Vdac3, m6A methylation, and ferroptosis in neurons during the hyperacute phase post-ICH and suggest novel therapeutic strategies for ICH.
