ErTao decoction alleviates liver fibrosis by suppressing STING-mediated macrophages and NLRP3 inflammasome activation

Background

Liver fibrosis (LF) is a common pathological process in the progression of multiple chronic liver diseases to cirrhosis, affecting millions of people worldwide annually. The incomplete understanding of its mechanisms has led to a lack of clinically effective therapeutic options. ErTao decoction (ETD, 二桃湯), a derivative combining the components of Erchen Decoction and Taohong Siwu Decoction, is rooted in the traditional Chinese medicine theory of "phlegm-dampness-blood stasis". However, the precise mechanism by which ETD exerts its therapeutic effects in LF remains unclear.

Purpose

The purpose of study was to investigate the protective effect of ETD and elucidate its underlying molecular mechanism on LF.

Methods

In this study, we employed a multifaceted approach to evaluate the effects of ETD on LF. We used H&E staining, Sirius red staining, immunofluorescence, immunohistochemical analysis, and Western blotting to assess the protective effects of ETD in a CCl4-induced fibrosis mouse model. In vitro validation was conducted using macrophages and hepatic stellate cells to further elucidate the mechanisms involved. STING-deficient mice were used to assess its regulatory effects on liver injury, inflammatory and activation through immunohistochemical staining and Western blotting. Furthermore, UHPLCHRMS detection and computer-aided drug analysis were employed to identify and validate potential effective components of ETD for responsible for its therapeutic effects in treating LF.

Results

In our in vivo and in vitro experiments, we found that ETD effectively reduced collagen fiber deposition and alleviated LF pathological changes by inhibiting macrophage inflammatory activation and suppressing NLRP3 and STING signaling. Notably, STING deficiency exhibited a protective effect against liver tissue injury and inhibited inflammatory activation of hepatic macrophages in LF model mice. Additionally, comprehensive analysis of the active ingredients in ETD strongly suggested that Naringin served as a pivotal bioactive constituent within ETD responsible for modulating STING signaling.

Conclusions

Our study highlighted the protective effects of ETD on LF by inhibiting STING-mediated macrophage activation and NLRP3 inflammasome signaling. Notably, Naringin might serve as a promising novel STING inhibitor to effectively counteract the progression of LF. These findings represented significant advances in LF research and paved the way for the development of novel therapeutic strategies.