{"doi":"10.1021/acs.jproteome.5c01004","title":"Phosphopeptidome Profiling of Human Plasma for Hepatocellular Carcinoma Biomarker Discovery","abstract":"Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality, and current biomarkers such as alpha-fetoprotein (AFP) lack diagnostic accuracy. Here, we report the first comprehensive profiling of the plasma endogenous phosphopeptidome in HCC, cirrhosis, and healthy controls using a digestion-free LC-MS/MS workflow. From 60 plasma samples, 1,365 phosphopeptides corresponding to 549 proteins were identified and quantified. Among these, the statherin-derived peptide DSSEEKFLR demonstrated outstanding discrimination between HCC and cirrhosis (AUC = 0.968), outperforming AFP (AUC = 0.648). Additional peptides, including PPGAPHTEEEGAE (NST1), YEYDELPAKDD (C4A), SLPGESEEMMEEVD (ITIH4), and VSLGSPSGEVSHPRKT (AHSG), also showed high accuracy (AUC > 0.80). Functional enrichment revealed perturbations in acute-phase response, coagulation, lipid metabolism, and LXR/RXR signaling. Collectively, this work defines a novel plasma phosphopeptide signature that reflects disease-specific proteolytic and phosphorylation dynamics, providing a foundation for developing biomarkers for early detection and clinical monitoring of HCC.","journal":"Journal of Proteome Research","year":2025,"id":587532,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8809,"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":1134105,"name":"Muhammad Sajid","orcid":"0000-0003-0176-7855","position":1,"is_corresponding":false},{"id":512994,"name":"Rency S. Varghese","orcid":"0000-0002-4236-7316","position":2,"is_corresponding":false},{"id":341379,"name":"Zaki A. Sherif","orcid":"0000-0002-1772-7041","position":3,"is_corresponding":false},{"id":239668,"name":"Alexander Kroemer","orcid":"0000-0002-9842-4973","position":4,"is_corresponding":false},{"id":311797,"name":"Habtom W. Ressom","orcid":"0000-0001-9296-2132","position":5,"is_corresponding":false},{"id":1503241,"name":"S M Saleem","orcid":"0000-0002-6653-8976","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:59:39.958043Z","pmid":"41474787","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":[]}