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ZFP36L1 Enhances Microglial Ferroptosis in Ischemic Stroke by Reducing FTO-Mediated N6-Methyladenosine Demethylation
Ai-Xia Song1,2, Han-Xu Jin2, Yuan-Xin Sun2
1Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China.
Abstract:
Microglia play an important role in ischemic stroke (IS). However, the molecular regulatory mechanisms underlying microglial ferroptosis in IS remain incompletely understood. In this study, blood samples were collected from 20 IS patients and 15 healthy volunteers. Microglia BV-2 subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) and mice undergoing middle cerebral artery occlusion-reperfusion (MCAO/R) surgery were used to establish IS models. Our results revealed that in blood samples from IS patients and in OGD/R-treated BV-2 cells, ZFP36 ring finger protein like 1 (ZFP36L1) and Acyl-CoA synthetase long chain family member 1 (ACSL1) expression was increased, while the fat mass and obesity-associated (FTO) protein expression was decreased. ACSL1 silencing attenuated ferroptosis and inflammation in OGD/R-treated microglia, as evidenced by decreased levels of malondialdehyde, Fe2+, lipid peroxidation, inflammatory factors, along with an increased Glutathione/Glutathione disulfide ratio. Additionally, ZFP36L1 silencing suppressed the OGD/R-induced promotion of ferroptosis and inflammation in microglia and alleviated cerebral ischemic injury in MCAO/R mice, whereas ACSL1 overexpression reversed these alterations caused by ZFP36L1 silencing. Mechanistically, ZFP36L1 decreased FTO messenger RNA (mRNA) stability and reduced FTO expression. FTO overexpression reduced ACSL1 N6-methyladenosine (m6A) modification and ACSL1 expression. In conclusion, ZFP36L1 increased ACSL1 m6A modification and ACSL1 expression to promote microglial ferroptosis, neuroinflammatory response, and cerebral ischemic injury in IS by reducing FTO mRNA stability.
Insights
ZFP36L1 promotes microglial ferroptosis and ischemic stroke injury by reducing FTO mRNA stability, leading to increased ACSL1 expression and modification. This highlights a novel regulatory pathway in ischemic stroke pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia are crucial in ischemic stroke (IS) pathogenesis.
- Molecular mechanisms of microglial ferroptosis in IS are not fully understood.
Purpose of the Study:
- To investigate the role of ZFP36L1, ACSL1, and FTO in microglial ferroptosis during ischemic stroke.
- To elucidate the regulatory pathway involving ZFP36L1, FTO, and ACSL1 in IS.
Main Methods:
- Collected blood samples from IS patients and healthy volunteers.
- Utilized oxygen-glucose deprivation/reoxygenation (OGD/R) in BV-2 microglia and middle cerebral artery occlusion-reperfusion (MCAO/R) in mice to model IS.
- Assessed ferroptosis, inflammation, gene expression, and m6A modification.
Main Results:
- ZFP36L1 and ACSL1 expression increased, while FTO decreased in IS patients and OGD/R-treated microglia.
- ACSL1 silencing attenuated microglial ferroptosis and inflammation.
- ZFP36L1 silencing suppressed ferroptosis, inflammation, and alleviated IS injury in mice.
- ZFP36L1 reduced FTO mRNA stability; FTO overexpression reduced ACSL1 m6A modification and expression.
Conclusions:
- ZFP36L1 promotes microglial ferroptosis and IS injury by reducing FTO mRNA stability, thereby increasing ACSL1 expression and m6A modification.
- This pathway contributes to neuroinflammation and cerebral ischemic injury in IS.
- Targeting the ZFP36L1/FTO/ACSL1 axis may offer therapeutic strategies for IS.
