Researchers have discovered that combining silybin and carvedilol is more effective against liver fibrosis than either drug alone. The pair targets key drivers of liver scarring, reducing collagen buildup in experimental models. Both drugs are already approved for other uses, paving the way for quick clinical testing.
Liver fibrosis affects hundreds of millions worldwide, often progressing to cirrhosis or liver cancer without approved treatments. It arises from repeated liver damage due to causes like viral hepatitis, alcohol, metabolic disorders, toxins, or autoimmune diseases, activating hepatic stellate cells (HSCs) that produce excess collagen scar tissue.
This process involves multiple signaling pathways, including TGF-β, PDGF, and Wnt/β-catenin, making single-drug therapies insufficient. A study published on December 15, 2025, in Targetome by a team led by Hong Wang and Haiping Hao at China Pharmaceutical University explores a combination approach. They found that silybin, which protects liver cells from injury, inflammation, and oxidative stress in models using ActD/TNFα, tBHP, and TNFα, has limited direct antifibrotic effects. In human LX-2 and rat HSC-T6 cells stimulated by TGFβ1, and in carbon tetrachloride-induced mouse fibrosis, silybin modestly reduced markers like COL1A1, COL1A2, ACTA2, and TGFB, mainly by safeguarding cells rather than halting HSC activation.
To enhance this, the team screened 397 FDA-approved drugs using a COL1A1-luciferase reporter system. Carvedilol emerged as the top synergist. Together, at a fixed 50:1 ratio (silybin to carvedilol), they sharply curtailed collagen production and HSC activation in cell cultures and primary cells, outperforming each alone. In mice, the duo dose-dependently lessened liver injury, inflammation, and fibrosis—more potently than obeticholic acid.
Mechanistically, the combination inhibits Wnt/β-catenin signaling by suppressing Wnt4 and β-catenin activity, explaining its efficacy. Both drugs are established, safe, and inexpensive, supporting rapid repurposing for this unmet need. The work, funded by Chinese national programs and foundations, also underscores phenotype-based screening's value in uncovering drug synergies.
