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

Brian K Chung; Markus S Jördens; Jonas Øgaard; Henrik Mikael Reims; Benedicte Flateland; Tom Luedde; Xiaojun Jiang; Tom H Karlsen; Espen Melum

doi:10.1097/HEP.0000000000001432

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

Hepatology. 2025 Jun 25. doi: 10.1097/HEP.0000000000001432. Online ahead of print.

Authors

Brian K Chung^{1

2

3}, Markus S Jördens^{1

2

3

4}, Jonas Øgaard^{1

2}, Henrik Mikael Reims⁵, Benedicte Flateland^{1

2

3}, Tom Luedde⁴, Xiaojun Jiang^{1

2}, Tom H Karlsen^{1

2

3

6}, Espen Melum^{1

2

3

6

7}

Affiliations

¹ Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery and Specialized Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
² Research Institute of Internal Medicine, Division of Surgery and Specialized Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
³ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁴ Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, University Hospital Düsseldorf, Düsseldorf, Germany.
⁵ Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁶ Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery and Specialized Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁷ Hybrid Technology Hub, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.

PMID: 40560681
DOI: 10.1097/HEP.0000000000001432

Abstract

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-related 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 in patients with PSC correlated with aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and bilirubin levels at 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.

Keywords: liver; single-nuclei RNA sequencing; spatial transcriptomics.