Mechanisms of Phillygenin and Forsythiaside A in Liver Fibrosis Based on Hepatocyte-Derived Exosomes

<p class="0000" style="margin-top: 6.0pt;"><a name="_Hlk193287421"></a><span lang="EN-US">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. <em>Forsythia suspensa</em> (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.</span>