Low-Abundance Proteomics Reveal Pleiotrophin and Fibroblast Growth Factor-21 as Biomarkers of Metabolic Dysfunction-Associated Steatohepatitis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to comorbidities like obesity, type 2 diabetes, and cardiovascular disease. Given that liver biopsy is the diagnostic gold standard, there is a critical need for minimally invasive tests, particularly for the inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH). In this discovery study, we investigated the plasma proteome to identify blood biomarkers for MASH and explored their potential tissue sources, the liver and visceral adipose tissue. Plasma low-abundance proteome profiling was performed on samples from a cohort of morbidly obese MASLD subjects (n = 90; 40 with MASH, 50 without) using Olink® panels. Paired liver and visceral adipose biopsies were also analyzed. Data showed 34 significantly different plasma proteins between the two groups, including Pleiotrophin (PTN), Fibroblast growth factor-21 (FGF-21), and Hepatocyte growth factor (HGF), among others. While plasma-tissue correlation was only found for STX8, PTN and FGF-21 demonstrated the strongest associations with the histopathological features of MASH. A diagnostic model combining PTN, FGF-21, and AST achieved a robust AUC of 0.88 (95% CI: 0.84–0.97) for distinguishing MASH. Based on this discovery pilot study, circulating PTN and FGF-21 emerge as promising non-invasive biomarkers for improving patient stratification and supporting therapeutic evaluation in MASH, warranting validation in independent cohorts and future studies.