Senolytics dasatinib and quercetin reversed liver scarring in 47% of MASH patients versus 7% on placebo in the first human senolytic trial confirmed by biopsy of the diseased organ itself
Senolytics dasatinib and quercetin reversed liver scarring in 47% of MASH patients versus 7% on placebo in the first human senolytic trial confirmed by biopsy of the diseased organ itself
A team at Amsterdam UMC conducted a 21-week double-blind placebo-controlled trial in 31 patients with biopsy-confirmed liver scarring (fibrosis). The results, published October 1 in Nature Metabolism, held up under two independent verification methods: both repeat biopsies and single-nucleus sequencing of liver cells showed the same shift in the treatment group.
Old, damaged liver cells stop dividing but do not die: they accumulate and spend years secreting inflammatory and fibrogenic signals that fuel the disease. These cells are called senescent, and drugs designed to selectively kill them are called senolytics. Dasatinib plus quercetin (D+Q) were first described as a senolytic combination in 2015 by James Kirkland and Tamar Tchkonia at the Mayo Clinic; both hold patents on these compounds, and ten years later they became co-authors of this study. D+Q had already been tested in humans with pulmonary fibrosis and diabetic kidney disease, but those trials assessed senescent cell clearance in fat, skin, and blood rather than the state of the diseased organ. In mice, senescent cell removal had already reversed liver fibrosis, and the liver has a rigorous diagnostic standard in biopsy; this is why the first direct organ-level test was done in the liver.
31 adults with confirmed MASH received either D+Q in intermittent courses (a total of 27 days of dosing over 21 weeks) or placebo. Paired biopsies taken before and after treatment were read blindly by three pathologists: fibrosis improved by at least one stage without worsening of MASH in 8 of 17 patients on D+Q versus 1 of 14 on placebo (47% versus 7%), and all histological signs of the disease itself resolved completely in 9 of 17 versus 1 of 14, without weight loss, the usual driver of improvement.
Single-nucleus sequencing of liver cells confirmed the same shift at the molecular level: in the D+Q group, the activity of senescence and collagen genes decreased, activation of hepatic stellate cells (the main source of scar tissue) dropped, the proportion of stellate and immune cells fell, and the proportion of normal hepatocytes rose; in the placebo group the opposite occurred. The investigators separately checked for liver cancer risk, since senescence sometimes acts as a barrier against tumors, but molecular pathways associated with cancer showed no increase in activity.
The authors describe the result as a hypothesis that remains to be confirmed: the relative risk of fibrosis improvement was 6.59, with a 95% confidence interval of 0.93 to 46.53, which formally admits the possibility of no effect. The D+Q group had twice as much type 2 diabetes at baseline and more advanced fibrosis, leaving more room for improvement. Blood markers and elastography showed no difference between groups; only biopsy detected the effect. Adverse events were nearly twice as frequent on D+Q (82% versus 43%, mainly headache and gastrointestinal upset), and some patients experienced a drop in platelets, an expected effect of dasatinib. This kind of clearance carries its own risks: in a 2020 mouse study, removal of a different population of senescent liver cells, primarily those lining the vasculature, damaged the liver's barriers and caused fibrosis.
Fatty liver disease affects nearly 40% of the world's population, and fibrosis in MASH is the main risk factor for cirrhosis, liver cancer, and death. D+Q has already been tested in older adults at risk for Alzheimer's disease in an open-label pilot trial that looked only at safety.
The decade-old senolytic hypothesis has met a pathologist's scalpel for the first time and survived its initial test, with eight responders out of seventeen. To move beyond hypothesis, senolytics need a large trial held to the same biopsy standard.