Liver fibrosis is a dynamic process characterized by excessive extracellular matrix (ECM) deposition due to chronic liver injury. Emerging evidence highlights the pivotal role of intercellular crosstalk in hepatic fibrogenesis, particularly via exosomes mediated communication. Forsythia suspensa (Thunb.) Vahl, a traditional Chinese herb with culinary uses such as in teas, congee, and soups, has garnered attention for its medicinal properties. Notably, its bioactive constituents, phillygenin (PHI) and forsythiaside A (FA), exhibit significant antifibrotic potential. This study aimed to investigate the therapeutic mechanisms of PHI and FA in liver fibrosis, focusing on their modulation of LO2 cell-derived exosomes and their subsequent effects on hepatic stellate cell (HSC) activation and macrophage polarization. Initially, we explored the efficacy of PHI and FA on liver fibrosis using a mouse model. We then validated the effects of PHI and FA in an LO2 cell injury model and explored the underlying mechanisms. To further elucidate intercellular interactions, we isolated LO2 cells-derived exosomes and assessed their impact on LX2 and THP-1 cells in co-culture systems. Our results revealed that PHI and FA alleviated liver fibrosis by inhibiting hepatocytes apoptosis, oxidative stress, and inflammatory responses. Furthermore, PHI and FA regulate LO2 cell-derived exosomes to suppress HSC activation and macrophage M1 polarization. In summary, this study elucidates how PHI and FA modulate hepatocyte-HSC-macrophage crosstalk, providing mechanistic insights into their antifibrotic actions. These findings contribute to the understanding of liver fibrosis pathogenesis and offer theoretical support for the development of novel antifibrotic therapies based on traditional Chinese medicine.

Chlorogenic acid (CA) is a natural plant-derived polyphenol compound that is widely present in beverages (coffee and tea), fruits (blueberry, apple, and mulberry), and medicinal plants (Lonicera japonica, Eucommia ulmoides, and Cichorium intybus). In recent years, CA has attracted extensive attention due to its various health benefits, such as anti-inflammatory, immunomodulatory, anti-obesity, anti-diabetes mellitus, and neuroprotection activities. Interestingly, the low bioavailability of CA corresponds to high bioactivity, which raises a key scientific question of how low bioavailability CA can achieve high biological activity. In this review, we highlight the gut microbiota as a key target for connecting the two by summarizing a large amount of evidence. Specifically, the composition and abundance of gut microbiota, its metabolites, intestinal immunity, barrier function and so on were all changed under different pathological conditions such as inflammatory bowel disease, liver disease, kidney disease, cardiovascular disease, diabetes mellitus, obesity, etc. Conversely, these changes could be reversed by CA. In a word, CA could achieve pharmacological activity as well as health-protective effects by modulating intestinal immune and barrier function, gut microbiota composition, gut microbiota metabolites, and signaling pathways. This review provides new targets for the prevention and treatment of diseases by CA. Meanwhile, regulating the composition of the gut microbiota through natural products may be a potential strategy to achieve health protection.

As a traditional Chinese herbal medicine, Schisandrae Chinensis Fructus (SC) has been used in medicine and food industry due to its health care and therapeutic effects. Over the past 20 years, the use of SC and its active ingredient lignans in the prevention and treatment of liver diseases has been increasing, and their hepatoprotective effects has increased the interest of the public and academia. Therefore, in the present work, we first determined the effectiveness of SC in the treatment of liver diseases such as metabolic associated fatty liver disease, alcoholic liver disease, cholestatic liver disease and acute liver injury. Subsequently, the pharmacological effects and molecular mechanisms of lignans, the active components of SC, for liver disease treatment were comprehensively summarized for the first time. The results showed that the lignans in SC could achieve hepatoprotective effects by regulating lipid metabolism, anti-fibrosis, anti-inflammation, anti-oxidation, anti-tumor and regulating bile acid metabolism. The mechanism mainly involved adenosine 5’-monophosphate-activated protein kinase, endoplasmic reticulum stress, sterol regulatory element binding protein 1c, autophagy, transforming growth factor-β, mitogen-activated protein kinase, microRNA, nuclear factor kappa-B, nuclear factor erythroid-2-related factor 2, heat shock proteins and pregnane X receptor signaling pathways. These results can lay a scientific foundation for the development of hepatoprotective drugs or functional foods from SC/lignans.