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Transcriptomic analysis of 372 HCC samples using publicly available datasets revealed that\n                    <jats:italic>SPP1<\/jats:italic>\n                    was significantly upregulated in fibrotic HCC tissues and associated with unfavorable outcomes. Immunohistochemical analysis of 103 HCC tissues and single\u2010cell RNA sequencing (scRNA\u2010seq) analysis of 228,564 live cells identified\n                    <jats:italic>SPP1<\/jats:italic>\n                    overexpression in HCC cells, which strongly correlated with intratumoral fibrosis. In xenograft models, HCC cells with SPP1 overexpression (SPP1\u2010OE) exhibited enhanced fibrosis and tumor growth. Coculture assay demonstrated that SPP1\u2010OE cells stimulated hepatic stellate cells (HSCs), and gene set enrichment analysis and differential gene expression analysis elucidated the activation of the Hedgehog signaling pathway and upregulation of\n                    <jats:italic>GLI1<\/jats:italic>\n                    in HSCs. Cell\u2013cell interaction prediction analysis using scRNA\u2010seq data suggested that SPP1\u2010CD44 signaling transduction might contribute to HSC activation. Pharmacological inhibition of GLI1 with the SMO inhibitor vismodegib suppressed HSC activation in\u00a0vitro and reduced fibrosis and tumor growth in\u00a0vivo. These findings indicate that SPP1 promotes intratumoral fibrosis and HCC progression through the SPP1\u2010CD44\u2010GLI1 axis, highlighting its potential as a prognostic biomarker and therapeutic target. Inhibition of SPP1\u2010CD44\u2010Hedgehog signaling may provide a promising strategy to mitigate fibrosis and improve HCC patient outcomes.\n                  <\/jats:p>","DOI":"10.1111\/cas.70296","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:57:45Z","timestamp":1766969865000},"page":"670-682","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting\n                    <scp>SPP<\/scp>\n                    1\u2010\n                    <scp>CD<\/scp>\n                    44\u2010Hedgehog Axis Elicits Therapeutic Effects in Hepatocellular Carcinoma by Suppressing Intratumoral Fibrosis"],"prefix":"10.1111","volume":"117","author":[{"given":"Atsushi","family":"Nara","sequence":"first","affiliation":[{"name":"Department of Molecular Oncology, Graduate School of Medicine Institute of Science Tokyo  Tokyo Japan"},{"name":"Department of Hepatobiliary and Pancreatic Surgery, 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