Prognostic Value of the TLM3 Biomarker Panel for Early Fibrosis Development in MASLD Within the General Population

Fibrotic MASLD is associated with increased morbidity and mortality, often remaining asymptomatic until advanced stages of disease. Predicting fibrosis onset and progression would improve risk stratification and treatment allocation. This study aims to investigate whether a previously identified fibrosis biomarker panel for active fibrogenesis (TLM3) can serve as a prognostic marker panel for fibrosis development in a population at cardiometabolic risk of fibrotic MASLD.

The temporal dynamics of a molecular fibrosis gene expression signature associated with histologically proven fibrosis development was investigated in a diet-induced MASLD mouse model (LDLr-/-.Leiden). The corresponding proteins were measured in baseline serum from individuals at risk of MASLD from the general population HELIUS-cohort and correlated with established fibrosis proxies (ELF, VCTE and FIB4) at 7 years follow-up.

The molecular fibrosis gene expression signature was upregulated in a murine MASLD model before the onset of histopathological features of fibrosis. In humans, serum levels of IGFBP7, Ssc5D, Sema4D, VCAN, THBS1 and TNC at baseline correlated with fibrosis proxies at follow-up. IGFBP7 at baseline was able to predict new onset fibrosis, defined as ELF ≥ 9.8 at follow-up in participants with ELF < 9.8 at baseline, with an area under the curve (AUC) of 0.79 (95% CI: 0.64-0.94).

Together, these findings indicate the potential predictive capacity of the TLM3 biomarker panel in early stages of MASLD-fibrosis, both in a murine model as well as in individuals from the general population at risk of MASLD.