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Introduction Liver biopsy is the reference standard for assessing disease severity in metabolic dysfunction-associated steatohepatitis (MASH), yet biopsies are rare in clinical practice. Given that non-invasive tests (NITs) are reasonable surrogates for assessing disease severity, this analysis utilized NITs and fibrosis stage from liver biopsy and assessed clinical outcomes.Methods This analysis included US adults in TARGET-NASH, a longitudinal observational study. Eligible participants had one liver biopsy and two FIB-4 measurements. Participants were classified into two subgroups based on longitudinal changes in FIB-4 category (<1.3, 1.3-2.67, >2.67) between the first and second assessment: stable/improved (no change/decrease in FIB-4 category) or worsened (increase in FIB-4 category). Fine-Gray multivariable subdistribution hazard models with time-varying covariates assessed the association between FIB-4 and time to clinical events.Results The analysis cohort (n=625) had a median age of 56, with 74% identifying as non-Hispanic White, 67% female, a median BMI of 33kg/m2, and 14.2% (n=89) and 85.8% (n=536) were classified in the worsened and stable/improved subgroups, respectively. The mean (SD) of first FIB-4 for each FIB-4 category was: 0.85 (0.26), n=227 for FIB-4<1.3; 1.92 (0.40), n=230 for FIB-4=1.3-2.67; and 4.90 (2.43), n=168 for FIB-4 >2.67. The worsened group had a higher incidence of cirrhosis (25.6%, incidence rate = 5.4 per 100 person-years) compared with the improved/stable group (p=0.044). Among those with non-cirrhotic MASH, a higher proportion experienced a composite of clinical events in the worsened group (44.8%) than the improved/stable group (24.5%, p=0.021). Participants with FIB-4 >2.67 had a higher risk of all-cause mortality (HR:6.02, 95% CI: 2.86-12.68), and 5.5 times the risk of progressing to cirrhosis (HR: 5.48, 95% CI:2.39-12.57) compared with those having FIB-4 <1.3.Conclusions Given the limitations of biopsy NITs like FIB-4 may be used to assess disease severity and disease progression. Changes in FIB-4 category were associated with differences in cirrhosis risk and clinical outcomes. These findings reinforce the potential role of FIB-4 as a non-invasive tool for risk assessment in MASH management.Abstract P60 Figure 1Cumulative incidence functions (CIFs) for MASL/MASH progression to cirrhosis and composite events stratified by the disease progression subgroups (unadjusted)