Plasma Biomarkers of Senescence in Cholestatic Liver Disease: A Signature of Risk Stratification and Progression

BACKGROUND AND AIMS: Cellular senescence is a hallmark of several liver diseases, including primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Senescent cholangiocytes exhibit a senescence-associated secretory phenotype (SASP), characterized by profibroinflammatory mediator release. Current cost-effective biomarkers predicting disease progression, particularly for PSC, are limited and often lack mechanistic relevance. We sought to define a plasma biomarker signature for PSC and PBC. METHODS: Plasma from early- and late-stage PSC and PBC, alcoholic liver disease (ALD), inflammatory bowel disease (IBD) patients, and healthy controls was analyzed. Seventy-one analytes were quantified using Luminex Multiplex Immunoassay or enzyme-linked immunosorbent assay (ELISA). Principal component analysis (PCA) identified key patterns. Findings from the PSC cohort were then applied to additional cohorts. RESULTS: Second principal component (PC2) (17 analytes, 17.1% variability) best separated PSC from controls. ANOVA showed significant differences in PC2 between early PSC vs. controls (p = 0.0001), late PSC vs. controls (p < 0.0001), and early vs. late PSC (p < 0.0001). PC2 analytes also distinguished early PBC vs. controls (p < 0.0332), late PBC (p < 0.0001), and ALD (p < 0.0001), and early vs. late PBC (p < 0.0001), but not IBD vs. controls (p = 0.119). Logistic regression using PC2 demonstrated strong discrimination of early- and late-stage PSC (AUC = 0.86) and control vs. early-stage PSC (AUC = 0.83). CONCLUSION: This is the first study to define a plasma SASP biomarker signature associated with cholestatic liver disease. These analytes track disease stage and represent both mechanistic indicators and potential clinical trial endpoints.