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

Cellular senescence plays an important role in hepatic inflammation and fibrosis1–3. 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 . In a double-blind, placebo-controlled trial, intermittent dasatinib and quercetin treatment over 21 weeks improves liver fibrosis in patients with MASH, as shown by paired liver biopsies, and reduces senescence and fibrotic gene signatures, as demonstrated by single-nucleus transcriptomics.

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Journal
Nature Metabolism
Published
2026-10-01
DOI
https://doi.org/10.1038/s42255-026-01643-4
Primary Topic
Liver Disease Diagnosis and Treatment
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article
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article

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

Bernd Schnabl, James L. Kirkland, Eliza J. M. Ruhé, Teaco Kuiper et al.
Nature Metabolism
Liver Disease Diagnosis and Treatment
article

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

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

Abstract

Cellular senescence plays an important role in hepatic inflammation and fibrosis1–3. 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 . In a double-blind, placebo-controlled trial, intermittent dasatinib and quercetin treatment over 21 weeks improves liver fibrosis in patients with MASH, as shown by paired liver biopsies, and reduces senescence and fibrotic gene signatures, as demonstrated by single-nucleus transcriptomics.

Nature Metabolism
Cedars-Sinai Medical Center (US), University of Antwerp (BE), Erasmus MC (NL), Amsterdam UMC Location University of Amsterdam (NL), University of California San Diego (US), Spaarne Ziekenhuis (NL), Antwerp University Hospital (BE), St. Antonius Ziekenhuis (NL), Flevoziekenhuis (NL), Groene Hart Ziekenhuis (NL), Haga Hospital (NL), Ziekenhuis Amstelland (NL), Amsterdam University Medical Centers (NL), Amsterdam Gastroenterology Endocrinology Metabolism (NL), Vrije Universiteit Amsterdam (NL), University of Amsterdam (NL), Rotterdam University of Applied Sciences (NL), Erasmus University Rotterdam (NL)
Good health and well-being
Openalex Percentile: Top 11%
Liver Disease Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
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