Hepatic methionine-cycle dysregulation is associated with immune-inflammatory and fibrogenic remodeling in biliary atresia.

BACKGROUND: Biliary atresia (BA) is a progressive fibroinflammatory cholangiopathy leading to liver failure in infancy. The contribution of methionine metabolism to BA remains incompletely defined. This study investigated hepatic methionine-cycle alterations and the potential therapeutic effects of S-adenosylmethionine (SAMe). METHODS: Public bulk transcriptomic and single-cell RNA sequencing datasets were analyzed to characterize methionine-cycle-related alterations in BA. Selected genes were validated in clinical liver tissues. Methionine-cycle metabolites, oxidative stress indicators, and histopathological changes were assessed in human liver samples. The effects of SAMe were examined in BA-derived liver mononuclear cells (LMNCs) and further evaluated in a rhesus rotavirus-induced BA mouse model using methionine-cycle metabolite quantification, liver transcriptomics, multiplex immunofluorescence, cytokine measurement, oxidative stress assays, and histological analysis. RESULTS: Methionine metabolism-related genes were dysregulated in BA, highlighting alterations in the one-carbon-methionine cycle-transsulfuration axis. Single-cell analysis localized these alterations to both hepatocyte and immune-cell compartments. Human BA liver tissues exhibited methionine-cycle imbalance, with increased methionine, S-adenosylhomocysteine, and homocysteine levels and reduced S-adenosylmethionine levels, accompanied by oxidative stress and fibrogenic responses. SAMe modulated cytokine secretion in BA-derived LMNCs. In BA mice, SAMe partially normalized methionine-cycle metabolite levels, improved hepatic redox status, reduced inflammatory immune infiltration, attenuated cytokine responses, and alleviated early fibrogenic remodeling. CONCLUSIONS: Hepatic methionine-cycle dysregulation is a prominent metabolic feature of BA and is associated with oxidative stress, immune-inflammatory alterations, and fibrogenic remodeling. SAMe partially alleviated these abnormalities in ex vivo and animal-model experiments, supporting further investigation of the therapeutic relevance of methionine metabolism in BA.