Vitamin A‑IntegratedCinnamaldehyde Nanoemulsion:A Nanotherapeutic Approach To Counteract Liver Fibrosis via Gut–LiverAxis Modulation

Liver fibrosis, a complex process resulting from most chronic liver diseases, remains devoid of effective treatments. An increasing body of evidence links liver fibrosis to the “gut–liver axis”, with disruptions in the gut microbiota–host balance emerging as a critical contributor to its progression. Cinnamaldehyde (Cin), a natural compound with antioxidant, anti-inflammatory, and anticytotoxic properties, has shown potential in counteracting hepatic stellate cell (HSC) activation. Additionally, Cin has been shown to promote probiotics in the intestine, thereby restoring a healthy microbial community. These characteristics position Cin as a promising candidate for liver fibrosis treatment through modulation of the gut–liver axis. In this study, a Vitamin A (Va)-formulated Cin Nanoemulsion (Va-Cin@NM) was developed to enhance the physicochemical stability of Cin while preserving intestinal homeostasis and facilitating targeted liver deposition. In bile duct ligation (BDL)-induced liver fibrosis in rats, Va-Cin@NM intervention significantly reduced bile duct-like structure proliferation and collagen deposition in the liver. These effects are likely attributed to the restoration of gut microbiota, increased short-chain fatty acid (SCFA) concentrations, and improved intestinal integrity. Moreover, Va-Cin@NM treatment suppressed harmful bacterial populations in the liver, thus mitigating immune injury and inflammatory cell recruitment. Consequently, oxidative stress and HSC activation were attenuated. Overall, Va-Cin@NM demonstrates significant potential as a nanotherapeutic approach for liver fibrosis by modulating the gut–liver axis.