ArticleCell biology and toxicology2024
METTL3 regulates TFRC ubiquitination and ferroptosis through stabilizing NEDD4L mRNA to impact stroke.
Article in Cell biology and toxicology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- Ubiquitination-dependent regulation of ferroptosis in ischemic heart and brain.Redox biology · 2026Review
- N 6 -methyladenosine modification regulates cell death in cognitive impairment.Neural regeneration research · 2026Article
- The role of N6-methyladenosine associated genes in ischemic stroke risk: interplay with environmental factors.Journal of thrombosis and thrombolysis · 2026Review
- Ferroptosis in Recurrent Vulvovaginal Candidiasis Through Integrated Bioinformatics and Experimental Validation.Antioxidants (Basel, Switzerland) · 2026Article
- METTL3-mediated m6A modification of FDX1 confers resistance to cuproptosis and promotes hepatocellular carcinoma progression.Communications biology · 2026Article
- The ketogenic diet alleviates neuronal ferroptosis in epilepsy via HDAC4/TFRC signalling.Archives of medical science : AMS · 2026Article
- The Emerging Role of METTL3 in Lung Diseases.International journal of molecular sciences · 2025Review
- IGF2BP1 positively regulates CircOGDH accumulation in hypoxia induced stress granules.Acta pharmaceutica Sinica. B · 2025Article
- METTL3-dependent mAutophagy · 2025Article
- LOXL1-AS1 suppresses ferroptosis in cervical cancer through m6A-dependent regulation of TFRC.Journal of molecular histology · 2025Article
- The Roles of E3 Ubiquitin Ligases in Cerebral Ischemia-Reperfusion Injury.International journal of molecular sciences · 2025Review
- METTL14 Promotes Ischemic Stroke-induced Brain Injury by Stabilizing HDAC3 Expression in an m6A-IGF2BP3 Mechanism.Cell biochemistry and biophysics · 2025Article
- Lactylation and Ischemic Stroke: Research Progress and Potential Relationship.Molecular neurobiology · 2025Review
- The Role and Mechanisms of Ubiquitin-Proteasome System-Mediated Ferroptosis in Neurological Disorders.Neuroscience bulletin · 2025Review
- Integrated Analysis and Validation of Ferroptosis-Related Genes Associated with Ischemia/Reperfusion Injury in Lung Transplantation.Journal of inflammation research · 2025Article
- Research progress of ferroptosis pathway and its related molecular ubiquitination modification in liver cancer.Frontiers in oncology · 2025Review
- NImmunity, inflammation and disease · 2024Review
- Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects.Signal transduction and targeted therapy · 2024Review
- RAB17 promotes endometrial cancer progression by inhibiting TFRC-dependent ferroptosis.Cell death & disease · 2024Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundStroke is a major medical problem, and novel therapeutic targets are urgently needed. This study investigates the protective role and potential mechanisms of the N6-methyladenosine (m6A) RNA methyltransferase METTL3 against cerebral injury resulting from insufficient cerebral blood flow.
methodsIn this study, we constructed mouse MCAO models and HT-22 cell OGD/R models to mimic ischemic stroke-induced brain injury and neuronal damage. We generated NEDD4L knockout and METTL3 overexpression models and validated therapeutic effects using infarct volume, brain edema, and neurologic scoring. We performed qRT-PCR, western blotting, and co-immunoprecipitation to assess the influence of NEDD4L on ferroptosis markers and TFRC expression. We verified the effect of NEDD4L on TFRC ubiquitination by detecting half-life and ubiquitination. Finally, we validated the impact of METTL3 on NEDD4L mRNA stability and MCAO outcomes in both in vitro and in vivo experimental models.
resultWe find NEDD4L expression is downregulated in MCAO models. Overexpressing METTL3 inhibits the iron carrier protein TFRC by upregulating the E3 ubiquitin ligase NEDD4L, thereby alleviating oxidative damage and ferroptosis to protect the brain from ischemic injury. Mechanistic studies show METTL3 can methylate and stabilize NEDD4L mRNA, enhancing NEDD4L expression. As a downstream effector, NEDD4L ubiquitinates and degrades TFRC, reducing iron accumulation and neuronal ferroptosis.
conclusionIn summary, we uncover the METTL3-NEDD4L-TFRC axis is critical for inhibiting post-ischemic brain injury. Enhancing this pathway may serve as an effective strategy for stroke therapy. This study lays the theoretical foundation for developing m6A-related therapies against ischemic brain damage.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.