{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T14:28:14Z","timestamp":1788532094086,"version":"build-2803163510"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100010722","name":"Harbin Medical University","doi-asserted-by":"publisher","award":["HYDSYJBGS2025-05"],"award-info":[{"award-number":["HYDSYJBGS2025-05"]}],"id":[{"id":"10.13039\/100010722","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007452","name":"Wu Jieping Medical Foundation","doi-asserted-by":"publisher","award":["230.6750.2022617"],"award-info":[{"award-number":["230.6750.2022617"]}],"id":[{"id":"10.13039\/100007452","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hepatocellular carcinoma (HCC) is a highly prevalent malignant tumor in China, and early diagnosis critically affects the prognosis. Current imaging and pathological biopsy techniques have limitations, including high invasiveness and limited accessibility, while the insufficient sensitivity of serum biomarkers (such as AFP) restricts their use in early screening. In this study, using the Olink proteomics platform based on the proximity extension assay (PEA), we screened for hepatocellular carcinoma-related differentially expressed proteins (DEPs) and constructed a multiprotein diagnostic model. In the discovery cohort, we included 15 patients with newly diagnosed HCCs and 16 healthy controls. DEPs were identified using Olink, and their diagnostic performance was analyzed to identify the candidate biomarkers. In an independent validation cohort, including 116 HCC patients (50 early stage, 66 late stage) and 83 healthy controls, we further validated the expression levels and diagnostic performance of identified proteins\u2500C1QA and GFER. The C1QA and GFER expression levels were significantly higher in the serum of patients with early and late HCC stages compared to healthy controls. By constructing a multiprotein diagnostic model, we identified C1QA, GFER, and AFP as the optimal diagnostic combination, demonstrating a combined diagnostic AUC of 0.92 and 0.99 for early-stage and advanced-stage HCC, respectively.<\/jats:p>","DOI":"10.1021\/acs.jproteome.6c00384","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T14:02:06Z","timestamp":1786716126000},"page":"4945-4956","source":"Crossref","is-referenced-by-count":0,"title":["Serum Olink\nProteomics Reveals Novel Biomarkers for\nEarly Diagnosis of Hepatocellular Carcinoma"],"prefix":"10.1021","volume":"25","author":[{"given":"Liliia","family":"Glazutdinova","sequence":"first","affiliation":[{"name":"The Fourth Affiliated Hospital of Harbin Medical University , , ,","place":["Harbin, China, 150001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Liu","sequence":"additional","affiliation":[{"name":"The Fourth Affiliated Hospital of Harbin Medical University , , ,","place":["Harbin, China, 150001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingchun","family":"Huang","sequence":"additional","affiliation":[{"name":"The Fourth Affiliated Hospital of Harbin Medical University , , ,","place":["Harbin, China, 150001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuyao","family":"Ji","sequence":"additional","affiliation":[{"name":"The Fourth Affiliated Hospital of Harbin Medical University , , ,","place":["Harbin, China, 150001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Wang","sequence":"additional","affiliation":[{"name":"The Fourth Affiliated Hospital of Harbin Medical University , , ,","place":["Harbin, China, 150001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaili","family":"Duan","sequence":"additional","affiliation":[{"name":"The Fourth Affiliated Hospital of Harbin Medical University , , ,","place":["Harbin, China, 150001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Gao","sequence":"additional","affiliation":[{"name":"The Fourth Affiliated Hospital of Harbin Medical University , , ,","place":["Harbin, China, 150001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[{"name":"The Fourth Affiliated Hospital of Harbin Medical University , , ,","place":["Harbin, China, 150001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0087-8327","authenticated-orcid":true,"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"The Fourth Affiliated Hospital of Harbin Medical University , , ,","place":["Harbin, China, 150001"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"issue":"3","key":"2026090409131405000_cit1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global Cancer Statistics 2022: GLOBOCAN\nEstimates of Incidence and Mortality Worldwide for 36 Cancers in 185\nCountries","volume":"74","author":"Bray","year":"2024","journal-title":"CA-Cancer J. Clin."},{"issue":"1","key":"2026090409131405000_cit2","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.jncc.2024.01.006","article-title":"Cancer Incidence\nand Mortality in China, 2022","volume":"4","author":"Han","year":"2024","journal-title":"J. Natl. Cancer\nCent."},{"issue":"5","key":"2026090409131405000_cit3","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1097\/SLA.0000000000000710","article-title":"Recurrence\nof Hepatocellular Cancer After Resection","volume":"261","author":"Tabrizian","year":"2015","journal-title":"Ann.\nSurg."},{"issue":"10","key":"2026090409131405000_cit4","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/s41575-019-0186-y","article-title":"A Global View of Hepatocellular Carcinoma:\nTrends,\nRisk, Prevention and Management","volume":"16","author":"Yang","year":"2019","journal-title":"Nat. Rev. Gastroenterol.\nHepatol."},{"issue":"4","key":"2026090409131405000_cit5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0095192","article-title":"Homogenous\n96-Plex PEA Immunoassay Exhibiting High Sensitivity, Specificity,\nand Excellent Scalability","volume":"9","author":"Assarsson","year":"2014","journal-title":"PLoS One"},{"key":"2026090409131405000_cit6","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2021.100168","article-title":"Proximity Extension\nAssay in Combination\nwith Next-Generation Sequencing for High-Throughput Proteome-Wide\nAnalysis","volume":"20","author":"Wik","year":"2021","journal-title":"Mol. Cell. Proteomics"},{"key":"2026090409131405000_cit7","unstructured":"Bureau of Medical\nAdministration, National Health Commission of the People\u2019s\nRepublic of China Standardization for Diagnosis and Treatment of Hepatocellular\nCarcinoma (2022 Edition) (in Chinese)\n          Zhonghua\nGan Zang Bing Za Zhi\n          2022; Vol. 21(2), , pp 143\u201316810.3760\/cma.j.cn115610-20220124-00053."},{"issue":"1","key":"2026090409131405000_cit8","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-021-00266-z","article-title":"Targeted Proteomics-Derived\nBiomarker Profile Develops a Multi-Protein Classifier in Liquid Biopsies\nfor Early Detection of Esophageal Squamous Cell Carcinoma from a Population-Based\nCase-Control Study","volume":"9","author":"Yang","year":"2021","journal-title":"Biomarker Res."},{"issue":"18","key":"2026090409131405000_cit9","doi-asserted-by":"publisher","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex Heatmaps\nReveal Patterns\nand Correlations in Multidimensional Genomic Data","volume":"32","author":"Gu","year":"2016","journal-title":"Bioinformatics"},{"issue":"9","key":"2026090409131405000_cit10","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20156297","article-title":"Revisiting Biomarker\nDiscovery by Plasma Proteomics","volume":"13","author":"Geyer","year":"2017","journal-title":"Mol. Syst. Biol."},{"issue":"6","key":"2026090409131405000_cit11","doi-asserted-by":"publisher","first-page":"5545","DOI":"10.18632\/aging.205663","article-title":"A Pyrimidine\nMetabolism-Related Signature for Prognostic and Immunotherapeutic\nResponse Prediction in Hepatocellular Carcinoma by Integrating Analyses","volume":"16","author":"Zhang","year":"2024","journal-title":"Aging"},{"key":"2026090409131405000_cit12","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.684961","article-title":"Targeting Pyrimidine\nMetabolism in the Era of Precision Cancer Medicine","volume":"11","author":"Wang","year":"2021","journal-title":"Front. Oncol."},{"key":"2026090409131405000_cit13","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1301473","article-title":"The Multiple\nRoles of C-Type Lectin Receptors in Cancer","volume":"13","author":"Li","year":"2023","journal-title":"Front. Oncol."},{"issue":"2","key":"2026090409131405000_cit14","doi-asserted-by":"publisher","first-page":"886","DOI":"10.3892\/or.2017.5738","article-title":"Intratumoral\nand Peritumoral Expression\nof CD68 and CD206 in Hepatocellular Carcinoma and Their Prognostic\nValue","volume":"38","author":"Ren","year":"2017","journal-title":"Oncol. Rep."},{"key":"2026090409131405000_cit15","doi-asserted-by":"publisher","first-page":"19","DOI":"10.2147\/JIR.S394503","article-title":"C-Type Lectin Receptors-Triggered\nAntifungal Immunity May Synergize with and Optimize the Effects of\nImmunotherapy in Hepatocellular Carcinoma","volume":"16","author":"Xia","year":"2023","journal-title":"J.\nInflamm. Res."},{"issue":"10","key":"2026090409131405000_cit16","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.1111\/jgh.16674","article-title":"Interleukin-1 Receptor 1 Deficiency\nWorsens Hepatocellular Carcinoma, While Gemcitabine Treatment Alleviates\nthe Hepatocellular Carcinoma-induced Increase in Intra-hepatic Immune\nCells","volume":"39","author":"Chu","year":"2024","journal-title":"J. Gastroenterol. Hepatol."},{"key":"2026090409131405000_cit17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02014","article-title":"Interleukin-1 Family\nCytokines: Keystones in Liver Inflammatory Diseases","volume":"10","author":"Barbier","year":"2019","journal-title":"Front. Immunol."},{"issue":"6","key":"2026090409131405000_cit18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005755","article-title":"Complement\nC1q Activates Tumor Suppressor\nWWOX to Induce Apoptosis in Prostate Cancer Cells","volume":"4","author":"Hong","year":"2009","journal-title":"PLoS One"},{"issue":"1","key":"2026090409131405000_cit19","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-48323-x","article-title":"C1QA and COMP: Plasma-Based\nBiomarkers for Early Diagnosis of Pancreatic Neuroendocrine Tumors","volume":"13","author":"Gorai","year":"2023","journal-title":"Sci. Rep."},{"key":"2026090409131405000_cit20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00865","article-title":"Is the Complement Protein\nC1q a Pro- or Anti-Tumorigenic Factor? Bioinformatics Analysis Involving\nHuman Carcinomas","volume":"10","author":"Mangogna","year":"2019","journal-title":"Front. Immunol."},{"issue":"1","key":"2026090409131405000_cit21","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-24353-9","article-title":"C1QA, C1QB, and GZMB Are Novel Prognostic\nBiomarkers of Skin Cutaneous Melanoma Relating Tumor Microenvironment","volume":"12","author":"Liang","year":"2022","journal-title":"Sci. Rep."},{"issue":"1","key":"2026090409131405000_cit22","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10346","article-title":"C1q Acts in the Tumour Microenvironment\nas a Cancer-Promoting Factor Independently of Complement Activation","volume":"7","author":"Bulla","year":"2016","journal-title":"Nat. Commun."},{"issue":"1","key":"2026090409131405000_cit23","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.smim.2013.04.003","article-title":"The Role of the Complement\nSystem in Metabolic Organs and Metabolic Diseases","volume":"25","author":"Phieler","year":"2013","journal-title":"Semin. Immunol."},{"issue":"1","key":"2026090409131405000_cit24","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-23240-6","article-title":"Complement\nC1q Stimulates the Progression\nof Hepatocellular Tumor through the Activation of Discoidin Domain\nReceptor 1","volume":"8","author":"Lee","year":"2018","journal-title":"Sci. Rep."},{"issue":"12","key":"2026090409131405000_cit25","doi-asserted-by":"publisher","first-page":"6717","DOI":"10.1073\/pnas.1918028117","article-title":"Complement C1q Mediates\nthe Expansion of Periportal Hepatic Progenitor Cells in Senescence-Associated\nInflammatory Liver","volume":"117","author":"Ho","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"4","key":"2026090409131405000_cit26","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1016\/j.jhep.2007.12.010","article-title":"Augmenter of Liver\nRegeneration: An Important Intracellular Survival Factor for Hepatocytes","volume":"48","author":"Thirunavukkarasu","year":"2008","journal-title":"J. Hepatol."},{"issue":"2","key":"2026090409131405000_cit27","first-page":"740","article-title":"Augmenter\nof Liver Regeneration Protein: A Promising Therapeutic Target for\nHepatocellular Carcinoma","volume":"12","author":"Hora","year":"2018","journal-title":"Asian J. Pharm."},{"issue":"5","key":"2026090409131405000_cit28","doi-asserted-by":"publisher","first-page":"3130","DOI":"10.3892\/or.2017.5984","article-title":"Decreased Expression\nof the Augmenter of Liver Regeneration Results\nin Growth Inhibition and Increased Chemosensitivity of Acute T Lymphoblastic\nLeukemia Cells","volume":"38","author":"Shen","year":"2017","journal-title":"Oncol. Rep."},{"issue":"10","key":"2026090409131405000_cit29","doi-asserted-by":"publisher","DOI":"10.1590\/1414-431x20176139","article-title":"Silencing\nof Augmenter of Liver Regeneration Inhibited Cell Proliferation and\nTriggered Apoptosis in U266 Human Multiple Myeloma Cells","volume":"50","author":"Zeng","year":"2017","journal-title":"Braz. J. Med. Biol. Res."},{"key":"2026090409131405000_cit30","doi-asserted-by":"publisher","first-page":"887","DOI":"10.2147\/OTT.S61531","article-title":"High Expression of\n23 KDa Protein of Augmenter of Liver Regeneration (ALR) in Human Hepatocellular\nCarcinoma","author":"Sheng","year":"2014","journal-title":"OncoTargets. Ther."},{"issue":"2","key":"2026090409131405000_cit31","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.intimp.2013.05.030","article-title":"Protective\nEffect of Augmenter of Liver Regeneration on Vincristine-Induced Cell\nDeath in Jurkat T Leukemia Cells","volume":"17","author":"Shen","year":"2013","journal-title":"Int. Immunopharmacol."},{"issue":"1","key":"2026090409131405000_cit32","first-page":"84","article-title":"Augmenter of Liver Regeneration Gene\nExpression in Human Colon Cancer Cell Lines and Clinical Tissue Samples","volume":"20","author":"Gatzidou","year":"2015","journal-title":"J. BUON"},{"issue":"2","key":"2026090409131405000_cit33","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.474","article-title":"Hepatocellular Carcinoma: Signaling Pathways, Targeted Therapy, and\nImmunotherapy","volume":"5","author":"Luo","year":"2024","journal-title":"MedComm"},{"issue":"4","key":"2026090409131405000_cit34","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.bbrc.2010.03.074","article-title":"Augmenter of Liver Regeneration Causes\nDifferent Kinetics of ERK1\/2 and Akt\/PKB Phosphorylation than EGF\nand Induces Hepatocyte Proliferation in an EGF Receptor Independent\nand Liver Specific Manner","volume":"394","author":"Ilowski","year":"2010","journal-title":"Biochem. Biophys.\nRes. Commun."},{"issue":"48","key":"2026090409131405000_cit35","doi-asserted-by":"publisher","first-page":"37443","DOI":"10.1074\/jbc.M004373200","article-title":"Stimulation of the Mitogen-Activated\nProtein Kinase Cascade and Tyrosine\nPhosphorylation of the Epidermal Growth Factor Receptor by Hepatopoietin","volume":"275","author":"Li","year":"2000","journal-title":"J. Biol. Chem."},{"issue":"1","key":"2026090409131405000_cit36","doi-asserted-by":"publisher","first-page":"109","DOI":"10.21873\/cgp.20564","article-title":"Augmenter of Liver\nRegeneration Enhances\nHepatocellular Carcinoma Cell Growth Through COX-2\u2013Associated\nSignaling","volume":"23","author":"Li","year":"2026","journal-title":"Cancer Genomics Proteomics"}],"container-title":["Journal of Proteome Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jproteome.6c00384","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/25\/9\/4945\/66543979\/acs.jproteome.6c00384.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/25\/9\/4945\/66543979\/acs.jproteome.6c00384.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T14:05:33Z","timestamp":1788530733000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jprobs\/article\/25\/9\/4945\/5255312\/Serum-Olink-Proteomics-Reveals-Novel-Biomarkers"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,8,14]]},"published-print":{"date-parts":[[2026,9,4]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jproteome.6c00384","relation":{},"ISSN":["1535-3893","1535-3907"],"issn-type":[{"value":"1535-3893","type":"print"},{"value":"1535-3907","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]}}}