Design and Synthesis of Betulinic Acid Derivatives as Antifibrotic Agents for Liver Fibrosis

Hepatic fibrosis is a major contributor to liver-related mortality and overall mortality. Currently, there is no established treatment for hepatic fibrosis. Research indicates that the transforming growth factor (TGF-β) signaling pathway is one of the key pathways involved in hepatic stellate cell (HSC) activation and fibrosis progression. Consequently, inhibiting the TGF-β signaling pathway represents a potential therapeutic strategy to combat hepatic fibrosis progression. <b>Betulinic acid</b> (BA) was widely extractable from natural plants, exhibits significant antifibrotic therapeutic effects. Three series of <b>BA</b> derivatives were synthesized and evaluated their antihepatic fibrosis activities. Most compounds showed no significant cytotoxicity <i>in vitro</i>. At nontoxic concentrations, these compounds effectively suppressed the TGF-β-induced upregulation of the liver fibrosis markers type I collagen and α-SMA. Notably, compound <b>3d</b> dose-dependently inhibited extracellular matrix (ECM) deposition in TGF-treated HSCs and suppressed HSC activation. These findings indicate that compound <b>3d</b>, acting as an antihepatic fibrosis agent, attenuates hepatic fibrosis by inhibiting the TGF-β signaling pathway.