Chronic
inflammation in response to persistent exogenous stimuli or damage results in
liver fibrosis, which subsequently progresses into malignant
liver diseases with high morbidity and mortality.
Ferulic acid (FA) is a
phenolic acid widely isolated from abundant plants and exhibits multiple
biological activities including
anti-oxidant, anti-
inflammation and enhancement of immune responses.
Adenosine monophosphate-activated
protein kinase (AMPK) functions as a critical energy sensor and is regulated through the phosphorylation of liver
kinases like LKB1 or dephosphorylation by
protein tyrosine phosphatases (
PTPs). However, the role of FA in
carbon tetrachloride (CCl4)-induced chronic
inflammation and
liver fibrosis and AMPK activation has not been elucidated. Here we reported that FA ameliorated CCl4-induced
inflammation and fibrotic liver damage in mice as indicated by reduced levels of serum liver function
enzyme activities and decreased expression of genes and
proteins associated with fibrogenesis. Additionally, FA inhibited hepatic oxidative stress, macrophage activation and HSC activation via AMPK phosphorylation in different liver cells. Mechanically, without the participation of LKB1, FA-induced anti-inflammatory and anti-fibrotic effects were abrogated by a specific
AMPK inhibitor, compound C. Combining with the results of molecular docking, surface plasmon resonance and co-immunoprecipitation assays, we further demonstrated that FA directly bound to and inhibited PTP1B, an
enzyme responsible for dephosphorylating key
protein kinases, and eventually leading to the phosphorylation of AMPK. In summary, our results indicated that FA alleviated oxidative stress, hepatic
inflammation and fibrotic response in livers through PTP1B-AMPK signaling pathways. Taken together, we provide novel insights into the potential of FA as a
natural product-derived therapeutic agent for the treatment of fibrotic liver injury.