Glutamine metabolism as a rheostat of CD4⁺ T cell pathogenic function in metabolic dysfunction-associated steatotic...

Metabolic dysfunction-associated steatotic liver disease (MASLD) severity is independently linked with pathogenic CD4⁺ T cell responses and skewed hepatic glutamine (Gln) metabolism. Whether these processes interact to drive disease progression remains unclear. Here, we identify hepatic Gln depletion as a key feature of steatohepatitis that is linked with increased hepatic CD4⁺ T cell inflammation and hepatocellular damage in humans. In complementary mouse models, both total hepatic and hepatic CD4⁺ T cell Gln levels were similarly reduced. Restoration of hepatic Gln through supplementation selectively restrained hepatic CD4⁺ T cell inflammatory programs and alleviated hepatocellular damage and disease severity. Mechanistically, T cell-intrinsic Gls1-mediated glutaminolysis limited O-GlcNAcylation to dampen pathogenic CD4⁺ T cell inflammation. Importantly, Gln treatment dampened CD4⁺ T cell-mediated injury in human liver organoids. Together, these findings establish hepatic CD4⁺ T cell-intrinsic Gln metabolism as a critical rheostat of pathogenic inflammation in MASLD and invoke metabolism-targeted strategies to restrict disease progression.