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.