Multimodal transcriptomics identifies metallothionein as a novel pathway in primary sclerosing cholangitis

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BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic inflammatory bile duct disorder of unknown etiology characterized by uneven peribiliary infiltration and liver fibrosis. To localize potential disease pathways to specific microanatomical liver regions, we combined spatial and single-nuclei transcriptomics (snRNA-seq) to analyze biopsies from a spectrum of PSC and disease control explants. APPROACH AND RESULTS: Liver specimens from 23 PSC (transplant indications: 4 recurrent cholangitis, 7 dysplasia, 12 cirrhosis) and 7 disease controls with cirrhosis (4 metabolic dysfunction-associated steatohepatitis, MASH; 3 alcohol-associated liver disease, ALD) were analyzed by spatial transcriptomics (76,664 spots) and 16 of the same explants were also assessed by snRNA-seq (12 PSC, 2 MASH, 2 ALD; 91,891 nuclei). PSC livers expressed a robust signature of metallothionein ( MT1E, MT1G , MT1H ) and acute inflammation markers ( SAA1 , SAA2 ) at the parenchyma-fibrosis interface compared to disease controls. SnRNA-seq showed that the strongest metallothionein signal originated from a subtype of APOE + hepatocytes that, by spatial transcriptomics and immunohistochemistry, were consistently localized to the edge of fibrotic lesions in PSC explants. Biliary inflammation induced by 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding in mice resulted in significant Mt1 liver expression and liver MT1G expression correlated with AST, ALT, ALP, and bilirubin levels at the time of liver transplantation. CONCLUSIONS: Combinatorial spatial and high-resolution single-nuclei transcriptomics on the largest number of PSC liver explants to date revealed metallothionein as a novel PSC pathway that could be interrogated in future studies aiming to develop effective therapeutic interventions for PSC.

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