BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder driven by obesity and metabolic dysfunction. MASLD progresses to metabolic dysfunction-associated steatohepatitis, which is characterized by inflammation, hepatocyte injury, and fibrosis, increasing the risk of cirrhosis and liver failure. Recent studies suggest that neutrophil extracellular traps (NETs) and extracellular DNA (ecDNA) contribute to liver inflammation and fibrogenesis. However, their role in MASLD pathogenesis remains incompletely understood. AIM: To investigate the dynamics of circulating NETs and ecDNA as potential biomarkers of liver injury in MASLD. METHODS: Using three complementary mouse models, thioacetamide (TAA)-induced fibrosis, choline-deficient L-amino acid-defined (CDAA) diet-induced metabolic dysfunction-associated steatohepatitis, and cafeteria (CAF) diet-induced MASLD, we assessed the association between NET-related markers and liver damage. Blood samples were collected biweekly to analyze ecDNA and NET markers, including myeloperoxidase (MPO) and MPO-DNA complexes, using ELISA and real-time PCR. Liver histopathology was assessed for inflammation, fibrosis, and neutrophil infiltration. RESULTS: The TAA and CDAA models exhibited significant liver injury, characterized by increased plasma alanine aminotransferase and aspartate aminotransferase levels, hepatocellular damage, and fibrosis. Elevated circulating NET markers (MPO and ecDNA) were observed in these models, with a strong correlation between NET formation and liver pathology. The CAF diet model induced steatosis but failed to elicit significant liver fibrosis or an increase in NET markers, suggesting that NETosis is associated with more severe liver damage. Notably, ecDNA and MPO levels correlated with neutrophil infiltration and fibrosis scores, indicating their potential as biomarkers of MASLD progression. CONCLUSION: NETosis and ecDNA levels reflect liver injury severity in MASLD. NET markers and liver fibrosis were strongly associated in TAA and CDAA models, whereas CAF model showed minimal NET involvement.