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HOXA5 Inhibits Microglia Pyroptosis in Cerebral Stroke by Regulating FTO-Mediated TMEM59 m6A Demethylation

Lin Mou1,2, Lei Zheng3, Bo Wang1

  • 1Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, P.R. China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|August 7, 2025
PubMed

Insights

HomeoboxA5 (HOXA5) deficiency exacerbates cerebral stroke by promoting microglia pyroptosis. HOXA5 upregulation inhibits neuroinflammation and brain injury by regulating FTO-mediated TMEM59 mRNA m6A modification.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Immunology

Background:

  • Microglia pyroptosis is a key driver of neuroinflammation and secondary brain injury following cerebral stroke.
  • Understanding the molecular mechanisms that regulate microglia pyroptosis is crucial for developing effective stroke therapies.

Purpose of the Study:

  • To investigate the role of homeoboxA5 (HOXA5) in regulating microglia pyroptosis during cerebral stroke.
  • To elucidate the molecular pathway through which HOXA5 influences neuroinflammation and brain injury.

Main Methods:

  • Cerebral stroke models were induced using middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) in rats.
  • Cell viability, pyroptosis, infarct size, and neuronal damage were assessed using MTT assays, flow cytometry, TTC staining, and FJB staining, respectively.
  • Molecular interactions were analyzed via MeRIP, dual luciferase reporter, ChIP, and RIP assays to examine HOXA5, FTO, YTHDF2, and TMEM59 interactions and m6A modification.

Main Results:

  • HOXA5 expression was found to be downregulated in cerebral stroke models.
  • Overexpression of HOXA5 significantly reduced cerebral injury, infarct size, and neuronal damage in MCAO-induced stroke.
  • HOXA5 upregulation inhibited MCAO and OGD/R-induced microglia pyroptosis.
  • HOXA5 was shown to transcriptionally activate FTO expression, which in turn prevented TMEM59 mRNA degradation by reducing YTHDF2-mediated m6A modification.

Conclusions:

  • HOXA5 plays a protective role in cerebral stroke by inhibiting microglia pyroptosis.
  • The HOXA5/FTO/YTHDF2/TMEM59 axis represents a novel therapeutic target for mitigating neuroinflammation and secondary brain injury in stroke.
Keywords:
HOXA5TMEM59cerebral strokem6Amicrogliapyroptosis

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