The study shows that this drug pair works far better together than either agent alone, offering a realistic and potentially fast path toward a new antifibrotic therapy.
Liver fibrosis is a silent yet widespread condition affecting hundreds of millions worldwide, and it can progress to cirrhosis or liver cancer. Despite decades of research, no antifibrotic drug has been approved for clinical use. Fibrosis arises when chronic or repeated liver injury—stemming from viral hepatitis, alcohol misuse, metabolic disease, toxins, or autoimmune disorders—triggers an exaggerated wound-healing response. A key driver is hepatic stellate cell (HSC) activation: normally quiescent HSCs switch into collagen-producing cells that promote extracellular matrix accumulation and scar formation. This transition is governed by multiple intersecting pathways, including TGF-β, PDGF, and Wnt/β-catenin signaling, making fibrosis highly complex. As single agents typically hit only one pathway, monotherapies often fall short, boosting interest in combination strategies that target multiple disease mechanisms simultaneously.
A study (DOI: 10.48130/targetome-0025-0009) published in Targetome on December 15, 2025 by Hong Wang's & Haiping Hao's team, China Pharmaceutical University, demonstrates that a clinically feasible, fixed-dose combination of silybin and carvedilol can synergistically suppress hepatic stellate cell activation and effectively reverse liver fibrosis by targeting Wnt4/β-catenin signaling, providing a promising new therapeutic strategy for a disease with no approved antifibrotic drugs.
To assess the therapeutic potential of silybin and overcome its limited antifibrotic efficacy, the study integrated in vitro and in vivo disease models with phenotype-based drug combination screening and mechanistic analyses. Initial experiments used hepatocyte injury models induced by ActD/TNFα, tBHP, and TNFα to characterize silybin's hepatoprotective profile. These assays demonstrated that silybin robustly restored cell viability, reduced reactive oxygen species accumulation, and suppressed inflammatory gene expression, confirming its strong antiapoptotic, antioxidative, and anti-inflammatory properties without detectable cytotoxicity. However, when its direct antifibrotic capacity was evaluated in TGFβ1-stimulated human LX-2 and rat HSC-T6 hepatic stellate cells, silybin only marginally reduced key fibrogenic markers, including COL1A1, COL1A2, ACTA2, and TGFB. Consistent with these findings, silybin treatment in carbon tetrachloride–induced fibrotic mice resulted in only modest improvements in serum transaminases, collagen deposition, and fibrotic gene expression, indicating that its antifibrotic benefits largely stem from indirect hepatoprotection rather than direct inhibition of HSC activation. To address this limitation, the researchers employed a COL1A1-luciferase reporter–based phenotype screening of 397 FDA-approved drugs in combination with silybin, identifying carvedilol as the most potent synergistic partner. This combination markedly suppressed collagen production and HSC activation in cultured human and rat HSCs as well as in primary hepatic stellate cells, consistently outperforming either monotherapy. Subsequent in vivo optimization revealed that a fixed-dose ratio of 50:1 (silybin to carvedilol) produced the strongest and most stable synergy, significantly improving liver injury, inflammation, and fibrosis severity in mice, with dose-dependent effects superior to obeticholic acid. Mechanistic investigations further demonstrated that this synergy arises from cooperative suppression of the Wnt/β-catenin signaling pathway, particularly through inhibition of the Wnt ligand Wnt4 and downstream β-catenin activity, establishing a clear molecular basis for the combination's robust antifibrotic efficacy.
This study highlights a clinically feasible antifibrotic strategy based on drug repurposing and rational combination therapy. Both silybin and carvedilol are already widely prescribed, have well-established safety profiles, and are inexpensive. Their combination could therefore move rapidly toward clinical testing, potentially addressing a major unmet medical need. Beyond liver fibrosis, the work also demonstrates how phenotype-based screening can uncover unexpected but powerful synergies between existing drugs.
