Lutein Attenuates Hepatic Stellate Cell Activation and Migration by Regulating miR-143-5p and Adenosine Deaminase

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and liver fibrosis is a key determinant of clinical outcomes during MASLD progression. Hepatic stellate cell (HSC) activation is the central driver of fibrosis through excessive extracellular matrix production. Although lutein, a xanthophyll carotenoid, has demonstrated hepatoprotective properties, its antifibrogenic effects and underlying molecular mechanisms in HSCs remain poorly understood. To investigate the antifibrogenic effects of lutein, LX-2 cells, a human HSC line, were pretreated with lutein and subsequently co-treated with transforming growth factor-β1 (TGF-β1) and lutein. Lutein significantly attenuated TGF-β1-induced HSC activation and cell migration. Mechanistically, small RNA sequencing showed that lutein suppressed the TGF-β1-induced upregulation of miR-143-5p. miR-143-5p inhibitor reduced fibrogenic marker expression and wound closure, indicating its role in HSC activation and migration. Label-free quantitative proteomics identified cell adhesion as a commonly enriched Gene Ontology term among proteins upregulated by TGF-β1 and downregulated by lutein. Of these proteins, adenosine deaminase (ADA) emerged as a key candidate mediator of the antifibrogenic effects of lutein. TGF-β1 increased ADA expression, which was attenuated by lutein. ADA inhibitor reduced TGF-β1-induced ACTA2 expression and cell migration. Collectively, these findings demonstrate that lutein attenuates HSC activation and migration, potentially through the regulation of miR-143-5p and ADA. These results provide new mechanistic insights into the antifibrogenic effects of lutein in HSCs and highlight its potential as a functional dietary compound for the prevention and treatment of liver fibrosis.