{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T18:16:34Z","timestamp":1778782594964,"version":"3.51.4"},"reference-count":66,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NHC Key Laboratory of Nuclear Technology Medical Transformation","award":["2024HYX001"],"award-info":[{"award-number":["2024HYX001"]}]},{"name":"Research and Innovation Fund of Wuhan Asia General Hospital","award":["2025KYCX1-B06"],"award-info":[{"award-number":["2025KYCX1-B06"]}]},{"name":"Open Project Fund of Hubei Key Laboratory of Embryonic Stem Cell Research","award":["2025ESOF003"],"award-info":[{"award-number":["2025ESOF003"]}]},{"name":"College Students' Innovative Entrepreneurial Training Plan Program of Hubei","award":["S202410488176"],"award-info":[{"award-number":["S202410488176"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Chronic hepatitis B virus (HBV) infection is a major etiology of hepatocellular carcinoma (HCC), with cancer stem cells (CSCs) playing a critical role in tumor progression and therapeutic resistance. However, the specific mechanisms linking HBV infection to stemness features in HBV-associated HCC (HBV-HCC) remain incompletely defined. To identify potential regulators, we conducted an integrated\n                    <jats:italic>in silico<\/jats:italic>\n                    multi-omics analysis using single-cell and bulk transcriptomic datasets. Comparative stemness scoring across major cell populations prioritized the endothelial compartment for further analysis. Subsequent pseudotime trajectory and CytoTRACE2 analysis of single-cell RNA sequencing (scRNA-seq) data identified Cluster 4 (C4) as a putative stemness-associated endothelial subpopulation, from which 21 differentially positive-HBV-expressed genes (DPEGs) were derived. In bulk RNA sequencing (bulk RNA-seq), weighted gene co-expression network analysis (WGCNA) identified genes strongly correlated with stemness in the blue module. Cross-referencing scRNA-seq and bulk RNA-seq yielded 52 shared genes. Random Forest feature selection prioritized two high-confidence biomarkers:\n                    <jats:italic>SSR2<\/jats:italic>\n                    and\n                    <jats:italic>UBE2D3<\/jats:italic>\n                    . A combined diagnostic model based on these two genes showed favorable performance across independent cohorts with bootstrap-supported validation, and survival analyses indicated that high\n                    <jats:italic>SSR2<\/jats:italic>\n                    expression and low\n                    <jats:italic>UBE2D3<\/jats:italic>\n                    expression were associated with poor clinical outcomes. Mechanistically, pathway activity correlation analyses revealed that\n                    <jats:italic>SSR2<\/jats:italic>\n                    and\n                    <jats:italic>UBE2D3<\/jats:italic>\n                    are significantly associated with endoplasmic reticulum stress (ERS), and mTOR signaling, suggesting a potential coordinated role in regulating viral persistence and stemness maintenance. Overall, our findings propose\n                    <jats:italic>SSR2<\/jats:italic>\n                    and\n                    <jats:italic>UBE2D3<\/jats:italic>\n                    as candidate diagnostic and prognostic biomarkers, providing a hypothesis-generating framework for developing targeted therapeutic strategies against HBV-HCC.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0349171","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T17:48:20Z","timestamp":1778780900000},"page":"e0349171","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Uncovering core stemness biomarkers in HBV-HCC through integrated multi-omics"],"prefix":"10.1371","volume":"21","author":[{"given":"Hanning","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7190-0749","authenticated-orcid":true,"given":"Xiaomei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"issue":"3","key":"pone.0349171.ref001","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"F Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"issue":"1","key":"pone.0349171.ref002","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"JM Llovet","year":"2021","journal-title":"Nat Rev Dis Primers"},{"issue":"7","key":"pone.0349171.ref003","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1136\/gutjnl-2023-330414","article-title":"HBV integrations reshaping genomic structures promote hepatocellular carcinoma","volume":"73","author":"Z Qian","year":"2024","journal-title":"Gut"},{"key":"pone.0349171.ref004","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhep.2016.02.021","article-title":"Mechanisms of HBV-induced hepatocellular carcinoma","volume":"64","author":"M Levrero","year":"2016","journal-title":"J Hepatol"},{"issue":"10","key":"pone.0349171.ref005","article-title":"Tenofovir vs Entecavir Among Patients With HBV-Related HCC After Resection","volume":"6","author":"P Li","year":"2023","journal-title":"JAMA Netw Open"},{"issue":"6217","key":"pone.0349171.ref006","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1126\/science.1260825","article-title":"Cancer etiology. 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