Senolytics dasatinib and quercetin in metabolic dysfunction-associated steatohepatitis: a proof-of-principle randomized, controlled trial.

Authors

Mijra Koning, Artemiy Kovynev, Marcos F Fondevila, Eliza J M Ruhe, Michiel C Mommersteeg, Christian Ramakers, Barbara A Hutten, Bart Verwer, Marije Vlug, Teaco Kuiper, Maarten van den Berg, Anne Vrieze, Maurice Bizino, Annewieke van den Beld, Luuk Berk, Thomas Boerlage, Quinten J J Augustijn, Willem Pieter Brouwer, Weena J Chen, Djuna Cahen, Robert Verdonk, Wouter J de Jonge, Sandjai Ramsoekh, Michail Doukas, Sanne M M Vermorgen, Joanne Verheij, Ulrich Beuers, R B Takkenberg, Jacques J G Bergman, Geert R A M D'Haens, Joost P H Drenth, Tamar Tchkonia, Bernd Schnabl, James L Kirkland, Abraham S Meijnikman

Published in

Nature metabolism. Oct 01, 2026. Epub Oct 01, 2026.

Abstract

Cellular senescence plays an important role in hepatic inflammation and fibrosis^1-3. However, whether senescence represents a potential therapeutic target in humans with metabolic dysfunction-associated steatohepatitis (MASH) remains unexplored. Here we report the results of a phase-2, double-blind, randomized, placebo-controlled trial of intermittent senolytic therapy with dasatinib plus quercetin (D + Q) in participants with fibrotic MASH. Thirty-one participants (median age 56 years; 76% male; 58% with type 2 diabetes) were randomized (1:1) to receive D + Q (dasatinib 100 mg per day plus quercetin 1,000 mg per day) or placebo for three consecutive days per week over 3 weeks, repeated across three 7-week cycles. The primary endpoint, ≥1 stage fibrosis improvement without MASH worsening on paired liver biopsies, is achieved in 47% of D + Q-treated participants versus 7% with placebo (P = 0.02). MASH resolution occurs more frequently with D + Q than placebo (53% versus 7%; P = 0.02), with a greater reduction in NAFLD Activity Score (-1.43 ± 1.22 versus -0.39 ± 0.77; P = 0.012). Single-nucleus RNA sequencing demonstrates decreased senescence and fibrotic gene signatures and reduced fibrogenic cell populations in the D + Q group. Although adverse events are more frequent in the D + Q group (82% versus 43%), these are all self-limiting. Overall, this proof-of-principle trial supports the need for future trials of senolytic therapy in fibrotic MASH. ClinicalTrials.gov identifier: NCT05506488 .

PMID:
42823536
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

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