Keisuke Sawada, Jarren R Oates, Masaki Kimura, Traci E Stankiewicz, John Eom, Pablo C Alarcon, Hak Chung, Michelle S M A Damen, Cassidy J Ulanowicz, Jennifer L Wayland, Ethan S O Williams Fonner, Colin C Anderson, Hayde K Cuervo-Jimenez, Amelia M Pearson, Yunguan Wang, Nathan Salomonis, Ty D Troutman, Julie A Reisz, Jeffrey C Rathmell, Sara Szabo, Michael A Helmrath, Takanori Takebe, Maria E Moreno-Fernandez, Senad Divanovic
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.