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Investigating the heterogeneity of relapsed HCC and identifying key therapeutic targets may facilitate the design of effective anticancer therapies. In this study, integrative analysis of single\u2010cell RNA sequencing data of primary and early\u2010relapsed HCC revealed increased proportions of infiltrating CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u00a0cells along with malignant cells and a decrease in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u00a0cells in relapsed HCC. Cellular interaction and immunohistochemical analysis proposed MIF\u2010(CD74\u2009+\u2009CXCR4) signaling pathway as a key mechanism by which malignant cells influence immune cells within the tumor microenvironment. Notably, primary malignant cells showed greater differentiation and proliferation potential, whereas relapsed cells exhibited enhanced epithelial\u2013mesenchymal transition and inflammation, along with upregulated glycogen synthesis and metabolism\u2010related gene expression. Using machine learning techniques on bulk RNA\u2010seq data, we developed a relapsed tumor cell\u2010related risk score (RTRS) that independently predicts overall and recurrence\u2010free survival time with higher accuracy compared with conventional clinical variables. Prognostic biomarkers and potential therapeutic targets were validated via RT\u2010qPCR using mouse implantation models. This comprehensive investigation elucidates the heterogeneity of relapsed HCC and constructs a novel postoperative recurrence prognostic model, paving the way for targeted therapies and improved patient outcomes.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70012","type":"journal-article","created":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T18:55:16Z","timestamp":1741460116000},"page":"2388-2411","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Exploration of heterogeneity and recurrence signatures in hepatocellular carcinoma"],"prefix":"10.1002","volume":"19","author":[{"given":"Wen\u2010Jing","family":"Wu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, Faculty of Medicine and Life Sciences, School of Life Sciences Xiamen University  Xiamen 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