Microfluidic human liver slices reveal antifibrotic effects of liraglutide via HSC deactivation and ECM remodeling.

BACKGROUND AND AIMS: Extracellular matrix (ECM) remodeling is a key driver of chronic liver disease (CLD) progression. Precision-cut liver slices (PCLS) offer a relevant ex vivo model, but their short-term viability under static conditions limits long-term studies. Microfluidic platforms improve tissue preservation and better mimic in vivo liver dynamics. Liraglutide has shown antifibrotic effects in non-cirrhotic patients, but its impact in cirrhosis remains unknown. This study aimed to establish a microfluidic human PCLS model and evaluate liraglutide's antifibrotic effects, focusing on ECM remodeling. METHODS: Human cirrhotic PCLS (ALD/MetALD) were cultured under static or microfluidic conditions. Viability, necrosis, fibrosis, and liver function were evaluated over 7 days. Collagen composition was analyzed in healthy, compensated, and decompensated liver samples. Cirrhotic PCLS were treated with liraglutide (200 µM) or vehicle, followed by transcriptomic and proteomic analyses. RESULTS: Microfluidic culture improved tissue integrity, reduced necrosis and fibrosis, and enhanced sinusoidal cells communication. Major collagens were upregulated in decompensated cirrhosis, while COL10α1 increased early in compensated stages. Liraglutide reduced fibrosis and rebalanced hepatic stellate cells (HSCs) phenotype, likely via metabolic reprogramming linked to inhibition of AKT signaling. CONCLUSION: Microfluidic hPCLS culture enables long-term preservation of cirrhotic liver tissue and supports functional drug testing. Liraglutide demonstrated antifibrotic activity through HSCs deactivation and ECM remodeling, independent of GLP1R signaling. COL10α1 emerged as a sensitive biomarker for fibrosis progression and regression, with potential utility in evaluating antifibrotic therapies.