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HIF-Mediated Fructose Metabolism and Disease Progression in the Cardiovascular-Kidney-Metabolic Syndrome

David Mathew1, Sean Davidson1, Derek Yellon1

  • 1The Hatter Cardiovascular Institute, University College London, London, UK.

Comprehensive Physiology
|August 11, 2025
PubMed

Insights

Fructose metabolism, regulated by Ketohexokinase-C, links cardiovascular-kidney-metabolic syndrome components. Inhibiting this pathway may improve cardiac outcomes in affected patients.

Area of Science:

  • Biochemistry
  • Pathophysiology
  • Cardiovascular Medicine

Background:

  • Cardiovascular-Kidney-Metabolic Syndrome involves multi-organ dysfunction and adverse cardiac events.
  • Fructose metabolism, via Ketohexokinase-C, is implicated in this syndrome's pathophysiology.
  • Cardiac Ketohexokinase-C expression is induced by HIF-1α during ischemia, leading to dysfunction.

Purpose of the Study:

  • To investigate the role of fructose metabolism in Cardiovascular-Kidney-Metabolic Syndrome.
  • To explore the potential cardiac effects of HIF-1α stabilization, particularly concerning Ketohexokinase-C.
  • To identify therapeutic targets for improving cardiac outcomes in this syndrome.

Main Methods:

  • Review of existing literature on fructose metabolism, organ crosstalk, and HIF-1α.
  • Analysis of the mechanistic links between fructose metabolism, inflammation, and organ dysfunction.
  • Consideration of clinical data regarding anemia treatments in chronic kidney disease.

Main Results:

  • Fructose metabolism is mechanistically linked to the Cardiovascular-Kidney-Metabolic Syndrome.
  • Cardiac Ketohexokinase-C expression, induced by HIF-1α, contributes to cardiac hypertrophy and dysfunction.
  • HIF-1α stabilizing drugs raise concerns due to potential pleiotropic cardiac effects.

Conclusions:

  • Fructose metabolism is a key player in the Cardiovascular-Kidney-Metabolic Syndrome.
  • Investigating the pleiotropic effects of HIF stabilization on cardiac physiology is crucial.
  • Pharmacological inhibition of Ketohexokinase-C presents a potential strategy to improve cardiac outcomes.

Keywords:
HIFKetohexokinasefructosehypoxia

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