Proteomic profiling of liver and plasma uncovers biomarkers and mechanisms in patients with primary biliary cholangitis

Primary biliary cholangitis (PBC) is a rare autoimmune liver disease that can progress to fibrosis and cirrhosis. As molecular biomarkers for PBC remain limited, we performed integrated liver and plasma proteomic analyses to identify disease-associated proteins, pathways, and candidate biomarkers. In this cross-sectional study, we recruited 15 patients with newly diagnosed PBC, 17 patients with metabolic dysfunction-associated steatotic liver disease (MASLD), and 19 healthy controls. Untargeted mass spectrometry-based proteomic analyses were performed on liver tissue and matched plasma samples. Differential expression and pathway enrichment analyses were used to characterise disease-associated proteomic alterations. As proof of concept, logistic regression-based machine learning models were used to evaluate whether proteomic signatures could distinguish PBC from MASLD and healthy controls. Selected proteins were evaluated in an independent United Kingdom Biobank (UKB) cohort. Here we show that 1917 liver and 102 plasma proteins are significantly altered in PBC compared with healthy controls, including 26 altered across tissues. Differentially abundant proteins are enriched in immune activation, biliary epithelial cell function, hepatic injury, and metabolic pathways. Plasma proteomics-based machine-learning models distinguish PBC from MASLD and healthy controls (area under the receiver operating characteristic curve 0.96 ± 0.06). Of the 20 proteins identified by the classification model, 12 are available in the UKB dataset, of which seven are significantly associated with PBC after adjustment for age, sex and BMI. Integrated liver and plasma proteomic analyses identify molecular pathways and circulating proteins associated with PBC. Further validation in larger, independent, age- and sex-matched cohorts is warranted. Primary biliary cholangitis (PBC) is a rare disease in which the immune system attacks the small bile ducts in the liver. Over time, this can cause scarring of the liver and liver failure. We studied proteins in liver tissue and blood to better understand the disease and identify proteins that may help distinguish PBC from other liver diseases. We analysed samples from people with newly diagnosed PBC, healthy volunteers, and people with metabolic dysfunction-associated steatotic liver disease. We identified changes in proteins linked to immune activity, liver injury, and metabolism. We also found that protein signals in blood could distinguish PBC from those in other groups. These findings improve our understanding of the disease and identify blood proteins that should be evaluated in larger studies. Kellemann et al. use integrated liver and plasma proteomics to characterize primary biliary cholangitis (PBC). The analyses identify immune and metabolic alterations and plasma protein signatures that distinguish PBC from metabolic dysfunction-associated steatotic liver disease (MASLD) and healthy individuals.