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Conventional surveillance and diagnostic strategies relying on imaging and alpha-fetoprotein (AFP) lack sufficient sensitivity, particularly for early-stage disease, underscoring the need for more accurate and minimally invasive approaches. Liquid biopsy has emerged as a promising investigational approach for early HCC detection and disease monitoring by enabling analysis of tumor-derived components in circulation. This review summarizes recent advances in liquid biopsy biomarkers for early-stage HCC, including genomic alterations in circulating tumor DNA (ctDNA), DNA methylation markers, circulating microRNAs, exosome-derived non-coding RNAs, and inflammatory markers. Established biomarkers such as AFP, together with complementary biomarkers including PIVKA-II, contribute to HCC risk assessment, while ctDNA alterations, particularly\n                    <jats:italic toggle=\"yes\">TERT<\/jats:italic>\n                    promoter and\n                    <jats:italic toggle=\"yes\">TP53<\/jats:italic>\n                    mutations, provide insight into early tumorigenesis and molecular heterogeneity. Aberrant methylation of tumor suppressor genes, including\n                    <jats:italic toggle=\"yes\">RASSF1A<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">SEPT9<\/jats:italic>\n                    , and\n                    <jats:italic toggle=\"yes\">CDKN2A<\/jats:italic>\n                    , represents early molecular events detectable in plasma. Circulating and exosomal microRNAs and long non-coding RNAs (lncRNAs) have demonstrated potential to improve diagnostic accuracy, particularly when incorporated into multi-marker panels. Importantly, these biomarkers vary in their level of clinical validation, ranging from guideline-integrated markers to emerging candidates that still require further standardization and prospective validation. Integrating validated biomarkers with novel epigenetic and RNA-based signatures holds substantial promise for improving early detection, patient stratification, and therapeutic decision-making in HCC.\n                  <\/jats:p>","DOI":"10.1177\/03936155261476073","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:07:37Z","timestamp":1790186857000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular biomarkers for early-stage hepatocellular carcinoma: Clinical applications beyond alpha-fetoprotein"],"prefix":"10.1177","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2017-138X","authenticated-orcid":false,"given":"Marah","family":"Amer","sequence":"first","affiliation":[{"name":"University of Padova"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9560-340X","authenticated-orcid":false,"given":"Valeria","family":"Tosello","sequence":"additional","affiliation":[{"name":"Veneto Institute of Oncology IOV-IRCCS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5658-942X","authenticated-orcid":false,"given":"Elisa","family":"Pinto","sequence":"additional","affiliation":[{"name":"Padua University Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.21037\/cco-20-162"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-024-02101-z"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-024-01021-z"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(22)00078-X"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-020-00381-6"},{"key":"e_1_3_5_8_2","first-page":"225","article-title":"NASH: The Emerging Most Common Form of Chronic Liver Disease","volume":"115","author":"Tesfay M","year":"2018","unstructured":"Tesfay M, Goldkamp WJ, Neuschwander-Tetri BA. 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