Discovery of Arenarine D and its active derivatives as a novel lead targeting DYRK1B/MYH9 in hepatic fibrosis

Hepatic fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components, which can potentially progress to cirrhosis and hepatocellular carcinoma. In this study, a natural product, Arenarine D, was isolated from the endophytic fungus Pallidocercospora crystallina of Ajuga decumbens Thunb. Mechanistic studies established DYRK1B and MYH9 as potential targets of Arenarine D. Through systematic structural optimization, we obtained a series of derivatives of Arenarine D. Among them, the active derivatives 8a, 5b, 11a, and 11b demonstrated enhanced anti-fibrotic activity to varying degrees in both TGF-β1 induced hepatic stellate cells (HSCs) activation models and hepatic fibrosis models induced by bile duct ligation (BDL) and carbon tetrachloride (CCl₄). These results underscore the potential of Arenarine D and its derivatives as valuable candidates for developing anti-hepatic fibrosis agents.