Liver-Targeted Scutellarin Nanoemulsion Alleviates Fibrosis with Ancillary Modulation of the Gut-Liver Microbiota

Liver fibrosis, a progressive condition with limited pharmacotherapies, poses a global health challenge. Scutellarin (SCU), a flavonoid derived from Erigeron breviscapus, has demonstrated anti-fibrotic activity and modulates gut microbiota. Emerging evidence suggests that SCU may also influence the hepatic microbiome. However, its clinical utility is constrained by poor water solubility and low oral bioavailability. Here, we developed an SCU-loaded nanoemulsion (SCE) to enhance solubility and liver-targeted delivery. In vitro, SCE increased SCU uptake in hepatic stellate cells (HSCs) and significantly inhibited TGF-β1-induced fibrogenesis. In a bile duct ligation (BDL) mouse model, oral administration of SCE improved hepatic SCU accumulation and produced superior anti-fibrotic efficacy. SCE treatment attenuated fibrosis and collagen deposition in the liver and improved liver function markers. Mechanistic investigations using 16S rRNA sequencing revealed that SCU treatment was associated with beneficial microbiota changes, although its main therapeutic effects were achieved through enhanced hepatic targeting. Notably, the SCE formulation was well-tolerated, showing no significant toxicity in vitro or in vivo. In conclusion, the SCU-loaded nanoemulsion achieved enhanced hepatic delivery of SCU and exerted potent anti-fibrotic effects via multiple mechanisms, including direct suppression of fibrogenesis and ancillary modulation of the gut-liver microbiome, offering a promising therapeutic strategy for liver fibrosis.