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Here we present a pilot spatial case series using sequencing-based spatial transcriptomics to examine alcohol-associated liver disease (ALD), metabolic dysfunction\u2013associated steatohepatitis (MASH), and chronic hepatitis C within preserved histological context. Eight liver tissues were profiled using a viral-aware workflow enabling in situ detection of hepatitis viral RNA, histology-guided niche annotation, and cell\u2013cell communication analysis; four cases passed quality control and were included in the core discovery analyses. In HCV case, viral reads localized to immune-enriched microenvironments and extended into adjacent regions enriched for cell-cycle, RNA-processing, and PD-1\u2013axis checkpoint pathways. In ALD and MASH tissues, histology-guided segmentation aligned with transcriptomic clusters, and pseudolobular sub-clustering identified recurrent functional compartments. Across the analyzed cases, immune\u2013mesenchymal signaling hubs associated with extracellular matrix and chemokine programs were observed. Overall, this pilot spatial case series suggests that chronic liver disease tissues may share recurrent pseudolobular functional architecture,  upon which etiology-associated immune, metabolic, and viral-response programs are superimposed in a case-dependent manner. Supplementary analyses summarize additional feasibility observations from HBV-profiled sections that did not support inclusion in the core downstream analyses.<\/jats:p>","DOI":"10.1038\/s41598-026-49400-7","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:30:52Z","timestamp":1776673852000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Spatial profiling of chronic liver disease: a pilot spatial case series"],"prefix":"10.1038","volume":"16","author":[{"given":"Shota","family":"Sasagawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Arihiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoichi","family":"Miura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Maejima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Ohsawa-Tatsuguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhito","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Tsuge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiro","family":"Oka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidewaki","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"49400_CR1","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.jhep.2023.03.017","volume":"79","author":"H Devarbhavi","year":"2023","unstructured":"Devarbhavi, H. et al. Global burden of liver disease: 2023 update. J. Hepatol. 79, 516\u2013537 (2023).","journal-title":"J. Hepatol."},{"key":"49400_CR2","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1097\/HEP.0000000000000387","volume":"80","author":"P Lin","year":"2024","unstructured":"Lin, P. et al. Single-cell and spatially resolved transcriptomics for liver biology. Hepatology 80, 698\u2013720 (2024).","journal-title":"Hepatology"},{"key":"49400_CR3","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/s41586-019-1631-3","volume":"575","author":"P Ramachandran","year":"2019","unstructured":"Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512\u2013518 (2019).","journal-title":"Nature"},{"key":"49400_CR4","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-55325-4","volume":"16","author":"BR Watson","year":"2025","unstructured":"Watson, B. R. et al. Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution. Nat. Commun. 16, 319 (2025).","journal-title":"Nat. Commun."},{"key":"49400_CR5","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-023-01218-y","author":"S Zhang","year":"2023","unstructured":"Zhang, S. et al. Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence. Genome Med. https:\/\/doi.org\/10.1186\/s13073-023-01218-y (2023).","journal-title":"Genome Med."},{"key":"49400_CR6","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1038\/s43018-024-00828-8","volume":"5","author":"L Lemaitre","year":"2024","unstructured":"Lemaitre, L. et al. Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease. Nat. Cancer 5, 1534\u20131556 (2024).","journal-title":"Nat. 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Molecular mechanisms of hepatocarcinogenesis following sustained virological response in patients with chronic Hepatitis C Virus infection. Viruses https:\/\/doi.org\/10.3390\/v10100531 (2018).","journal-title":"Viruses"},{"key":"49400_CR10","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1002\/hep.24001","volume":"52","author":"H Tilg","year":"2010","unstructured":"Tilg, H. & Moschen, A. R. Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology 52, 1836\u20131846 (2010).","journal-title":"Hepatology"},{"key":"49400_CR11","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1053\/j.gastro.2011.09.002","volume":"141","author":"B Gao","year":"2011","unstructured":"Gao, B. & Bataller, R. Alcoholic liver disease: Pathogenesis and new therapeutic targets. Gastroenterology 141, 1572\u20131585 (2011).","journal-title":"Gastroenterology"},{"key":"49400_CR12","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.jhep.2018.03.018","volume":"69","author":"European Association for the Study of the, L.","year":"2018","unstructured":"European Association for the Study of the, L. EASL clinical practice guidelines: Management of alcohol-related liver disease. J. Hepatol. 69, 154\u2013181 (2018).","journal-title":"J. Hepatol."},{"key":"49400_CR13","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","volume":"42","author":"Y Hao","year":"2024","unstructured":"Hao, Y. et al. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat. Biotechnol. 42, 293\u2013304 (2024).","journal-title":"Nat. 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