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AH is a complex disease encompassing the dysregulation of many cells and cell subpopulations. This study used a hepatic spatial transcriptomic and proteomic approach (10X Genomics Visium) to identify hepatic cell populations and their associated transcriptomic and proteomic alterations in human AH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Formalin\u2010fixed paraffin\u2010embedded liver tissue from AH patients (<jats:italic>n<\/jats:italic>\u2009=\u20092) and non\u2010ALD controls (donors) (<jats:italic>n<\/jats:italic>\u2009=\u20092) were used for Visium spatial transcriptomic and proteomic analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>AH cell clusters and cell markers were drastically different in regard to tissue pattern and number of cell types compared to non\u2010ALD controls. Cholangiocytes, endothelial cells, macrophages, and stellate cells were more profuse in AH relative to non\u2010ALD controls. Transcriptionally, proliferating cell nuclear antigen\u2010positive (PCNA<jats:sup>+<\/jats:sup>) hepatocytes in AH more closely resembled cholangiocytes suggesting they were non\u2010functional hepatocytes derived from cholangiocytes. Furthermore, mitochondria protein\u2010coding genes were reduced in AH versus non\u2010ALD control hepatocytes, suggesting reduced functionality and loss of regenerative mechanisms. Macrophages in AH exhibited elevated gene expression involved in exosomes as compared to non\u2010ALD controls. The most upregulated macrophage genes observed in AH were those involved in exosome trafficking. Gene and protein signatures of disease\u2010associated hepatocytes (<jats:italic>ANXA2<\/jats:italic><jats:sup><jats:italic>+<\/jats:italic><\/jats:sup><jats:italic>\/CXCL1<\/jats:italic><jats:sup><jats:italic>+<\/jats:italic><\/jats:sup><jats:italic>\/<\/jats:italic>CEACAM8<jats:sup>+<\/jats:sup>) were elevated in AH and could visually identify a pre\u2010malignant lesion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study identified global cell type alterations in AH and distinct transcriptomic changes between AH and non\u2010ALD controls. These findings characterize cellular plasticity and profuse transcriptomic and proteomic changes that are apparent in AH and contribute to the identification of novel therapeutics.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.15494","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T03:11:04Z","timestamp":1732677064000},"page":"106-116","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Visium spatial transcriptomics and proteomics identifies novel hepatic cell populations and transcriptomic signatures of alcohol\u2010associated hepatitis"],"prefix":"10.1111","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2191-9107","authenticated-orcid":false,"given":"Tyler C.","family":"Gripshover","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Louisville School of Medicine  Louisville Kentucky 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