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

Area of Science:

• Hepatology and immunology
• Molecular biology
• Genomics

Background:

• Primary sclerosing cholangitis (PSC) is a chronic bile duct inflammation with unknown causes.
• PSC involves peribiliary infiltration and liver fibrosis, impacting liver function.
• Understanding PSC's microanatomical pathways is crucial for targeted therapies.

Purpose of the Study:

• To localize potential disease pathways within specific liver regions in PSC.
• To investigate the role of metallothionein in PSC pathogenesis.
• To identify novel therapeutic targets for primary sclerosing cholangitis.

Main Methods:

• Spatial transcriptomics and single-nuclei RNA sequencing (snRNA-seq) were performed on liver explants.
• Analysis included 23 PSC and 7 disease control explants.
• A mouse model of biliary inflammation was used to validate findings.

Main Results:

• PSC livers showed elevated metallothionein (MT1E, MT1G, MT1H) and acute inflammation markers (SAA1, SAA2) at the parenchyma-fibrosis interface.
• Metallothionein expression was highest in APOE+ hepatocytes at fibrotic lesion edges in PSC.
• In mice, biliary inflammation increased Mt1 expression, correlating with liver injury markers.

Conclusions:

• Metallothionein represents a novel pathway in primary sclerosing cholangitis.
• Combinatorial transcriptomics revealed metallothionein's specific localization in PSC liver tissue.
• This finding opens avenues for developing new therapeutic interventions for PSC.