Deep proteome profiling of metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects roughly 1 in 3 adults and is a leading cause of liver transplants and liver related mortality. A deeper understanding of disease pathogenesis is essential to assist in developing blood-based biomarkers. Here, we use data-independent acquisition mass spectrometry to assess disease-state associated protein profiles in human liver, blood plasma, and white adipose tissue (WAT). In liver, we find that MASLD is associated with an increased abundance of proteins involved in immune response and extracellular matrix (ECM) and a decrease in proteins involved in metabolism. Cell type deconvolution of the proteome indicates liver endothelial and hepatic stellate cells are the main source of ECM rearrangements, and hepatocytes are the major contributor to the changes in liver metabolism. In the blood, profiles of several MASLD-associated proteins correlate with expression in WAT rather than liver and so could serve as suitable liver disease predictors in a multi-protein panel marker. Moreover, our proteomics-based logistic regression models perform better than existing methods for predicting MASLD and liver fibrosis from human blood samples. Our comprehensive proteomic analysis deepens the understanding of liver function and MASLD pathology by elucidating key cellular mechanisms and multi-organ interactions, and demonstrates the robustness of a proteomics-based biomarker panel to enhance diagnosis of MASLD and significant fibrosis. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition affecting about 1 in 3 adults. It occurs when there is too much fat in the liver, and is a leading cause of death and people needing liver transplants. To improve early detection, we studied proteins in the liver, blood, and fat of people with MASLD. Our analysis revealed changes in liver proteins and that certain proteins in the blood could serve as early indicators of liver disease. Some of the protein changes in the blood indicated changes in fat tissue rather than the liver. We propose that our blood test could be more accurate than commonly used methods for diagnosing early MASLD and so could enable better, non-invasive ways to detect liver disease. Boel et al. undertake a proteomic analysis of liver, plasma, and white adipose tissue from obese patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Key protein signatures are identified across different organs that offer a proteomic biomarker panel which is more accurate than other diagnostic methods.