Researchers recruited 15 patients with newly diagnosed PBC (primary biliary cholangitis), 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.
Patients with PBC were older than those with MASLD and healthy individuals and were predominantly female.
Researchers found extensive molecular changes in PBC, specifically, 1,917 liver proteins and 102 plasma proteins were significantly altered in PBC compared with healthy controls.
When comparing PBC to healthy individuals,1917 liver proteins and 102 plasma proteins were found to be significantly up-or downregulated
Proteins related to immune activation, inflammation, antigen presentation, and interferon signalling were increased in PBC, whereas proteins involved in hepatic metabolism and liver synthetic function and transferrin, were reduced.
In liver tissue from patients with PBC, multiple proteins involved in the innate immune response and interferon signalling were significantly upregulated. Several immunoglobulin components were also increased in both liver and plasma.
The plasma-based model achieved an AUC of 0.96 ± 0.06, indicating high discrimination between PBC and controls, and performed as well as or better than liver-based models.
Enrichment analysis showed predominantly immune- and inflammation-related processes in plasma, whereas liver tissue showed enrichment of pathways related to mitochondrial function, energy metabolism, and tissue remodelling.
Plasma proteomic profiles achieved classification performance comparable to that of liver tissue.
The researchers suggested that proteomics could help advance the diagnosis and biological understanding of PBC by identifying molecular changes linked to immune activation, bile duct dysfunction and disrupted liver metabolism.
The proteins identified by the researchers could serve as potential biomarkers to support earlier and more accurate differentiation of PBC from metabolic-associated steatotic liver disease and healthy individuals.
Further studies using untargeted proteomic platforms could also help confirm the full classification model and determine its potential role in improving patient stratification, diagnosis and disease monitoring.
Reference:
Kellemann J et al. Proteomic profiling of liver and plasma uncovers biomarkers and mechanisms in patients with primary biliary cholangitis. Commun Med.2026. DOI;10.1038/s43856-026-01924-9.
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