2. Academic Validation
  3. Axin-1, modified by IGF2BP2-dependent m6A, triggers neuronal ferroptosis in delayed encephalopathy animal model caused by carbon monoxide poisoning via Smurf1-mediated BDNF ubiquitination

Axin-1, modified by IGF2BP2-dependent m6A, triggers neuronal ferroptosis in delayed encephalopathy animal model caused by carbon monoxide poisoning via Smurf1-mediated BDNF ubiquitination

  • Brain Res Bull. 2025 Dec:233:111624. doi: 10.1016/j.brainresbull.2025.111624.
Shaokun Wang 1,  Jingchun Han 1,  Nan Gao 2,  Yingbo Wang 1,  Li Pang 3
Affiliations

Affiliations

  • 1 Department of Emergency, The First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China.
  • 2 Medical Quality Control Office, The Third Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin Province 130118, PR China.
  • 3 Department of Emergency, The First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China. Electronic address: [email protected].
PMID: 41205712 DOI: 10.1016/j.brainresbull.2025.111624
Abstract

Background: Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is a common complication after carbon monoxide poisoning. This study focused on the role and mechanism of Axin-1 regulating Ferroptosis in DEACMP.

Methods: Nissl staining, immunohistochemistry, immunofluorescence and Prussian blue were used to evaluate the histopathology and iron distribution of DEACMP rats. The N6-methyladenosine (m6A) level of Axin-1 was analyzed by m6A-RNA immunoprecipitation and qPCR (MeRIP-qPCR). The mRNA and protein levels of the molecules were tested by RT‑qPCR and Western blot. RNA immunoprecipitation (RIP) and Co-immunoprecipitation (Co-IP) experiments were used to verify the interaction between molecules. Cell viability and Apoptosis were detected using Cell counting kit-8 (CCK-8) and Terminal deoxynucleotidyl transferase dUTP nick (TUNEL) staining. Reactive Oxygen Species (ROS) levels were measured by flow cytometry. The levels of Lactate Dehydrogenase (LDH), malondialdehyde (MDA), glutathione (GSH), and Fe2+ were evaluated by biochemical kits.

Results: The expression of Axin-1 in DEACMP rats was increased, and its up-regulation was related to IGF2BP2-mediated m6A modification. Overexpression of Axin-1 abolished the protective inhibition of IGF2BP2 depletion-mediated oxidative damage and Ferroptosis induced by oxygen and glucose deprivation/reoxygenation (OGD/R) in hippocampal neurons. Axin-1 promoted the ubiquitination and degradation of BDNF by targeting Smurf1. Overexpressed Axin-1 inhibited the protective effect of BDNF on oxidative damage and Ferroptosis. The Nrf2/HO-1 pathway played a role in OGD/R-triggered Ferroptosis, which was mediated by Axin-1. The IGF2BP2/Axin-1 axis also regulated Ferroptosis in vivo.

Conclusion: IGF2BP2-mediated m6A modification of Axin-1 promoted oxidative damage and neuronal Ferroptosis by modulating Smurf1/BDNF and Nrf2/HO-1 pathways in DEACMP animal model and OGD/R cell model. Therefire, Axin-1 may be a potential therapeutic target for the treatment of DEACMP.

Keywords

Axin-1; IGF2BP2; carbon monoxide poisoning; delayed encephalopathy; ferroptosis; m(6)A.

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