Perillyl alcohol alleviates liver fibrosis by promoting hepatic stellate cell ferroptosis and inhibiting macrophage recruitment.

Abstract

BACKGROUND: The activation of hepatic stellate cells (HSCs) represents a critical progression in the development of liver fibrosis. Perillyl alcohol (POH), a naturally occurring monoterpene abundant in plant essential oils, demonstrates anti-inflammatory, antioxidant, and antitumor properties. However, the potential effect of POH in the treatment of liver fibrosis remains unclear. PURPOSE: In this study, we explored the suppressive effect of POH on HSCs activation and its underlying mechanism. METHODS: To explore the effects of POH, CCl4-induced liver fibrosis mouse model and primary HSCs were applied in the in vitro and in vivo experiments. HSC activation-markers and fibrotic markers were examined to evaluate the inhibitory effect on HSC activation after POH treatment via qRT-PCR, Western Blot, and Immunofluorescence staining assays. The mechanism by which POH inhibits HSC activation and exerts anti-fibrotic effects via the ferroptosis pathway was explored. RESULTS: POH attenuated CCl4-induced liver fibrosis in mice and suppressed HSC activation in vitro by inducing ferroptosis (characterized by intracellular iron overload, reactive oxygen species accumulation, malondialdehyde levels increase, and glutathione depletion). Mechanistically, these effects depended on the GPX4/NRF2 axis and consequently suppressed macrophage recruitment and hepatic inflammation. CONCLUSION: Collectively, our findings demonstrate that POH induces HSC ferroptosis through suppression of the NRF2/GPX4 pathway, which in turn inhibits macrophage recruitment and alleviates liver inflammation, highlighting its potential as a therapeutic option for liver fibrosis.

Key Findings

• Perillyl alcohol (POH) attenuates CCl4-induced liver fibrosis in mice.
• POH suppresses hepatic stellate cell (HSC) activation by inducing ferroptosis characterized by iron overload, ROS accumulation, increased malondialdehyde, and glutathione depletion.
• The anti-fibrotic effects of POH depend on the suppression of the NRF2/GPX4 pathway, which also reduces macrophage recruitment and hepatic inflammation.

Clinical Significance

Citation

Lin Shuangnv, Wang Meng, Pan Jinget al.. Perillyl alcohol alleviates liver fibrosis by promoting hepatic stellate cell ferroptosis and inhibiting macrophage recruitment. Chemico-biological interactions. 2026-Jul-25.