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Beyond energy: how TCA cycle-derived metabolites regulate gene expression and inflammation in the nucleus

Jaiya Randhawa1, Eva M Pålsson-McDermott2

  • 1School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland. randhawj@tcd.ie.

Journal of Inflammation (London, England)
|September 27, 2025
PubMed

Insights

TCA cycle metabolites like acetyl-CoA and α-ketoglutarate have dual roles, acting in the nucleus to control inflammation by modifying DNA and histones. This nuclear function impacts inflammatory diseases and cancers.

Area of Science:

  • Immunometabolism
  • Epigenetics
  • Molecular Biology

Background:

  • Immune cells dynamically alter metabolism upon stimulation.
  • Mitochondrial and nuclear communication is crucial for metabolic control.
  • Emerging evidence highlights metabolic intermediates with nuclear roles.

Purpose of the Study:

  • To review the non-canonical nuclear functions of TCA cycle metabolites.
  • To explore their role in regulating inflammation.
  • To discuss links to disease pathogenesis, including cancer.

Main Methods:

  • Literature review of studies on TCA cycle metabolites in the nucleus.
  • Analysis of mechanisms linking metabolite function to chromatin modification.
  • Synthesis of data on disease associations.

Main Results:

  • TCA cycle metabolites (acetyl-CoA, α-ketoglutarate, succinate, fumarate, itaconate, succinyl-CoA) exhibit nuclear moonlighting.
  • These metabolites directly modify DNA and histones.
  • These modifications regulate gene expression impacting inflammatory responses.

Conclusions:

  • Nuclear functions of TCA cycle metabolites are key regulators of inflammation.
  • Dysregulation of these functions contributes to inflammatory diseases and cancer.
  • Targeting these pathways may offer therapeutic strategies.
Keywords:
EpigeneticsImmunometabolismInflammationMetabolitesTCA cycle

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