{"doi":"10.1111/liv.70325","title":"Serum Proteomic Profile Based on the TGF‐β Pathway Stratifies Risk of Hepatocellular Carcinoma","abstract":"BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths, primarily due to late-stage diagnosis. In this multicenter study, our goal is to identify functional biomarkers that stratify the risk of HCC in patients with cirrhosis (CP) for early diagnosis. METHODS: Five thousand and eight serum proteins (Somascan) were analysed in Cohort A (477 CP, including 125 HCC). Clustering analysis of the TGF-β pathway-associated protein signature was performed in a longitudinal, prospective Cohort B (312 CP, in which 18 cases developed HCC over a 5-year follow-up period). Next, a multivariable prediction model was built using logistic regression analysis of cross-sectional data from a matched subgroup (n = 328, Cohort C). Model performance was 10-fold cross-validated across the entire Cohort A (n = 477). RESULTS: Longitudinal follow-up analysis revealed that patients with elevated TGF-β-related protein signature displayed a five-fold increased risk of developing HCC (9.68% vs. 1.91%). Compared to cirrhosis, serum MSTN, TGFBR2, and AFP levels raised in HCC were validated by ELISA (n = 200, odds ratio = 1.4-2.9, p < 0.05). In Cohort C, 88 proteins were significantly altered in HCC compared to cirrhosis (p < 0.05). The six-protein panel (TGFBR2, MSTN, AFP, COL18A1, GLUL, TP63) displayed a strong performance in the matched cohort C (AUC 0.87, sensitivity 0.88, specificity 0.72), alongside four clinical factors (Age, Sex, BMI, Bilirubin). A 10-fold cross-validation demonstrated a mean AUC of 0.86 in cohort A, with strong predictive power in obese/MASLD/ALD-related patients (AUCs: 0.862-0.921). CONCLUSIONS: The mechanism-based panel effectively stratifies HCC risk in cirrhotic patients, underscoring the need for Phase II/III validation.","journal":"Liver International","year":2025,"id":546729,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.5374,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":715182,"name":"Kirti Shetty","orcid":"0000-0002-7725-6050","position":1,"is_corresponding":false},{"id":291917,"name":"Herbert Yu","orcid":"0000-0003-3950-4815","position":2,"is_corresponding":false},{"id":1226002,"name":"Bibhuti Nath Mishra","orcid":"0000-0002-3355-7716","position":3,"is_corresponding":false},{"id":298944,"name":"Linda L. Wong","orcid":"0000-0003-3143-5384","position":4,"is_corresponding":false},{"id":311812,"name":"Xianghong Jasmine Zhou","orcid":"0000-0002-4522-7490","position":5,"is_corresponding":false},{"id":334547,"name":"Sanjaya K. Satapathy","orcid":"0000-0003-0153-2829","position":6,"is_corresponding":false},{"id":94667,"name":"James M. Crawford","orcid":"0000-0002-8581-1093","position":7,"is_corresponding":false},{"id":496149,"name":"Patricia S. Latham","orcid":"0000-0003-2782-9444","position":8,"is_corresponding":false},{"id":241808,"name":"Steven‐Huy B. Han","orcid":"0000-0003-1459-8763","position":9,"is_corresponding":false},{"id":699837,"name":"Bino Mathew","orcid":null,"position":10,"is_corresponding":false},{"id":1438828,"name":"Nabil N. Dagher","orcid":"0000-0002-8973-6588","position":11,"is_corresponding":false},{"id":334556,"name":"Lawrence Lau","orcid":"0000-0001-5892-6963","position":12,"is_corresponding":false},{"id":1439226,"name":"Fellanza Cacaj","orcid":null,"position":13,"is_corresponding":false},{"id":1033742,"name":"Anil K. Vegesna","orcid":"0000-0003-0097-4369","position":14,"is_corresponding":false},{"id":250569,"name":"Srinivasan Dasarathy","orcid":"0000-0003-1774-0104","position":15,"is_corresponding":false},{"id":333695,"name":"Aiwu Ruth He","orcid":"0000-0002-2104-0816","position":16,"is_corresponding":false},{"id":1226003,"name":"Hai Huang","orcid":"0000-0003-2123-6533","position":17,"is_corresponding":false},{"id":372455,"name":"Richard Amdur","orcid":"0000-0002-4900-653X","position":18,"is_corresponding":false},{"id":420257,"name":"Lopa Mishra","orcid":"0000-0002-6850-0808","position":19,"is_corresponding":false},{"id":623438,"name":"Xiyan Xiang","orcid":"0000-0002-4746-9522","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T02:53:36.567932Z","pmid":"40919824","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}