Obacunone, a
limonin triterpenoid extracted from Phellodendronchinense Schneid or Dictamnus dasycarpusb Turcz plant, elicits a variety of pharmacological effects such as anti-inflammatory, anti-neoplastic, anti-oxidation, and anti-lung-
fibrosis ones. However, the anti-fibrotic effect of
obacunone and the detailed underlying mechanism in
liver fibrosis remain unclear.
Liver fibrosis is a debilitating disease threatening human health.
Transforming growth factor (TGF)-β/P-Smad is a major pathway of
fibrosis featured with epithelia mesenchymal transformations (EMT) and
collagen depositions, accompanying with excessive
oxygen-
free radicals. Nrf-2 acts as a key anti-oxidative regulator driving the expressions of various
antioxidant-related genes. Glutathionperoxidase-4 (GPx-4) is a member of the
glutathione peroxidase family that directly inhibits
phospholipid oxidation to alleviate oxidative stress. In the present study, we aimed to explore the role of
obacunone in mouse
liver fibrosis model induced by
carbon tetrachloride (CCl4) and in hepatic stellate cells (LX2 cell line) challenging with TGF-β.
Obacunone demonstrated potent ameliorative effects on
liver fibrosis both in activated LX2 and in mice liver tissues with reduced levels of α-SMA, collagen1, and
vimentin.
Obacunone also remarkably suppressed the TGF-β/P-Smad signals and EMT process. Meanwhile,
obacunone exerted a potent anti-oxidation effect by reducing the levels of
reactive oxygen species (ROS) in both models. The
antioxidant effect of
obacunone was attributed to the activation of GPx-4 and Nrf-2. In addition, the
therapeutic effect of
obacunone on LX2 cells was significantly removed in vitro plus with GPx-4 antagonist RSL3, in parallel with the re-elevated levels of ROS. Thus, we demonstrate that
obacunone is able to attenuate
liver fibrosis via enhancing GPx-4 signal and inhibition of the TGF-β/P-Smad pathway and EMT process.