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The ZFP36-FTO axis is a key regulator of macrophage activation and a druggable therapeutic target of sepsis

Rajesh Sarkar1, Lei Wang1, Jie Du1

  • 1Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA.

Iscience
|December 16, 2025
PubMed

Insights

ZFP36 deletion causes inflammation by affecting FTO, while FTO inhibition reduces inflammation. This reveals the ZFP36-FTO pathway as a target for sepsis treatment.

Area of Science:

  • Immunology
  • Molecular Biology
  • Epigenetics

Background:

  • ZFP36 (Zinc Finger Protein 36) regulates N6-adenomethylation (m6A) status.
  • The ZFP36-FTO axis role in macrophage activation and systemic inflammation is not fully understood.

Purpose of the Study:

  • To investigate the role of ZFP36 and FTO in macrophage activation and systemic inflammation during sepsis.
  • To determine if FTO is a druggable target for sepsis treatment.

Main Methods:

  • Utilized Zfp36 knockout (KO) and Fto KO mouse models.
  • Employed bone-marrow-derived macrophages (BMDMs) challenged with lipopolysaccharide (LPS).
  • Analyzed NF-κB signaling, cytokine induction, and mRNA methylation status (m6A).

Main Results:

  • Zfp36 deletion in macrophages led to excessive systemic inflammation and NF-κB overactivation.
  • Fto ablation suppressed systemic inflammation and NF-κB signaling in sepsis models.
  • The ZFP36-FTO axis controls Socs1 mRNA m6A status, regulating macrophage activation.
  • FTO inhibition effectively reduced macrophage cytokine production and systemic inflammation.

Conclusions:

  • ZFP36 promotes Fto mRNA degradation, regulating m6A status in macrophages.
  • The ZFP36-FTO pathway is a critical regulator of macrophage activation and sepsis-induced inflammation.
  • FTO is a druggable target for the treatment of sepsis.
Keywords:
Biological sciencesBiopharmaceuticalsHealth sciencesRegulatory pharmacy

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