Metabolic benefits of ketohexokinase inhibition in individuals with MASLD: a randomized placebo-controlled crossover trial.

Authors

Evi J C Koene, Vera B Schrauwen-Hinderling, Jeremy Basset-Sagarminaga, Kim Brouwers, Yvonne M H Op den Kamp-Bruls, Julian Mevenkamp, Florian Haans, Gert Schaart, Esther Kornips, Johanna A Jorgensen, Jean L J M Scheijen, Casper G Schalkwijk, Michel van Weeghel, Frédéric M Vaz, Riekelt H Houtkooper, Elva Wong, Sander Kersten, Aditi R Saxena, William P Esler, Patrick Schrauwen, Martijn C G J Brouwers

Published in

Nature metabolism. Oct 07, 2026. Epub Oct 07, 2026.

Abstract

High fructose consumption, particularly from sugar-sweetened beverages, contributes to cardiometabolic disease. Here we study the metabolic effects of 6-week pharmacological inhibition with PF-06835919 of ketohexokinase, the enzyme that catalyses the first committed step of fructose metabolism, in a randomized placebo-controlled crossover trial in 15 participants with metabolic dysfunction-associated steatotic liver disease. The primary outcome was hepatic insulin sensitivity, measured by insulin-stimulated suppression of endogenous glucose production. Secondary outcomes included fat distribution, peripheral and adipose tissue insulin sensitivity, and fat oxidation. While PF-06835919 treatment did not affect body weight, it improved hepatic insulin sensitivity and reduced intrahepatic lipid and saturated fatty acid content. Besides these beneficial hepatic effects, PF-06835919 also improved insulin-stimulated glucose disposal, adipose tissue insulin sensitivity, adipose tissue distribution and nocturnal fat oxidation. These changes are accompanied by changes in very low-density lipoprotein particle size distribution and circulating hepatokines. These results show that inhibition of fructose metabolism has beneficial metabolic effects that extend beyond the organs that metabolize fructose. ClinicalTrials.gov identifier: NCT05463575 .

PMID:
42844400
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.

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