Glucagon-like peptide-1 receptor agonist dulaglutide attenuates liver injury in metabolic dysfunction-associated steatotic liver disease with diabetic mice.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease encompassing a spectrum of pathologies, including simple steatosis, steatohepatitis, fibrosis, and cirrhosis. Dulaglutide, a glucagon-like peptide-1 receptor agonist approved for diabetes treatment, has been investigated for its potential in MASLD management. This study aimed to assess the effects of dulaglutide and elucidate its potential mechanisms in a db/db mouse model of MASLD. METHODS: The efficacy of dulaglutide was evaluated in db/db mouse model of MASLD. After a 10-week treatment, hepatic function, histopathology, ferroptosis-related markers, inflammation, fibrosis, and dulaglutide-induced hepatic lipidomic alterations were assessed. RESULTS: Dulaglutide reduced serum ALT and AST levels and attenuated hepatic ferroptosis-related markers, as reflected by altered ACSL4 and GPX4 expression. ROS staining and Fe quantification demonstrated that dulaglutide mitigated elevated oxidative stress and iron accumulation in db/db mice. In parallel, dulaglutide treatment was associated with upregulation of GSH and Nrf2, as well as downregulation of MDA and 4-HNE, indicating reduced lipid peroxidation. Lipidomics analysis showed extensive remodeling of the hepatic lipid profile in db/db mice following dulaglutide treatment. In addition, dulaglutide reduced the expression of inflammatory and fibrotic markers in the db/db mouse model. CONCLUSION: These findings indicate that dulaglutide modulates ferroptosis-related markers, inflammation, and fibrosis in MASLD mice, supporting its potential as a therapeutic option for MASLD.