Journal of gastroenterology and hepatology · 2026
Plasma Biomarkers of Senescence in Cholestatic Liver Disease: A Signature of Risk Stratification and Progression.
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O'Hara Steven P, Bogert Pamela Tietz, Dickinson Stephanie, Chen Xiwei, Allison David B, Netto Jair Machado Espindola, Kirkland James L, Tchkonia Tamara, Ashraf Humza M, Morgenthaler Olivia, Ali Ahmad H, Lazaridis Konstantinos N, Gores Gregory J, LaRusso Nicholas
Аннотация
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.
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.