This study investigated whether hepatic glutamine (Gln) depletion drives CD4+ T cell-mediated inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD), using human liver tissue, complementary mouse models, and human liver organoids.
Hepatic Gln depletion was a key feature of steatohepatitis linked to increased CD4+ T cell inflammation and hepatocellular damage; Gln supplementation selectively restrained hepatic CD4+ T cell inflammatory programs and alleviated disease severity, with the mechanism involving T cell-intrinsic GLS1-mediated glutaminolysis limiting O-GlcNAcylation to dampen pathogenic inflammation.
Mouse models may not fully recapitulate human MASLD immunopathology; human liver organoid data, while promising, are ex vivo and cannot substitute for clinical trials; the study does not establish optimal dosing or safety of systemic Gln supplementation in patients.
Glutamine metabolism in hepatic CD4+ T cells acts as a critical brake on pathogenic inflammation in MASLD; targeting this pathway with Gln supplementation may offer a metabolism-based strategy to slow disease progression, pending clinical validation.
