{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:26:51Z","timestamp":1785421611589,"version":"3.56.0"},"reference-count":36,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T00:00:00Z","timestamp":1781913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22fk0210066h0103"],"award-info":[{"award-number":["JP22fk0210066h0103"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"award":["JP22fk0210066h0103"],"award-info":[{"award-number":["JP22fk0210066h0103"]}],"id":[{"id":"https:\/\/ror.org\/004rtk039","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["JP18H02661"],"award-info":[{"award-number":["JP18H02661"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"award":["JP18H02661"],"award-info":[{"award-number":["JP18H02661"]}],"id":[{"id":"https:\/\/ror.org\/048rj2z13","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Hamamatsu University School of Medicine"},{"id":[{"id":"https:\/\/ror.org\/00ndx3g44","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Abnormalities in energy and amino acid metabolism are potentially involved in hepatocellular carcinoma (HCC) development. This study aimed to identify serum metabolites predictive of HCC following sustained virological response (SVR) with hepatitis C virus (HCV) treatment. Methods: Comparative metabolomics was conducted using time-course serum samples from patients who failed interferon-based therapy but subsequently achieved SVR with direct-acting antivirals (DAAs), minimizing inter-individual variability. Predictive biomarkers for post-SVR HCC were extracted from the results and validated by comparing 29 patients who developed post-SVR HCC with 58 age-matched patients who remained HCC-free during follow-up. Results: Metabolite concentrations changed more markedly after treatment in SVR cases than in non-SVR cases. Significant changes in methionine (Met), methionine sulfoxide (MetO), and ornithine (Orn) levels before and after treatment (Pre- and Post-Tx) were found only in the non-HCC group. Regression and survival analyses identified high levels of Pre- and Post-Tx Orn, Pre-Tx Met, and Post-Tx MetO as predictors of post-SVR HCC and enabled risk stratification. The integration of these metabolites with the fibrosis-4 (FIB-4) index and alpha-fetoprotein (AFP) facilitated risk stratification and discriminated between high- and low-risk patients. The Pre-Tx FIB-4\/Met model and the Post-Tx AFP\/MetO\/Orn model identified low- and high-risk groups with 3-year HCC incidence rates of 6.4% and 81.8%, respectively. Conclusions: Serum Met, MetO, and Orn were identified as candidate biomarkers associated with post-SVR HCC development, which remains a concern in the fight against hepatitis C. Combining these metabolites with established clinical markers may improve post-SVR HCC risk stratification.<\/jats:p>","DOI":"10.3390\/cancers18122003","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:13:37Z","timestamp":1782195217000},"page":"2003","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolomics Approach Identifies Predictive Serum Markers for Hepatocellular Carcinogenesis Following Hepatitis C Virus Elimination"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6389-0528","authenticated-orcid":false,"given":"Takeshi","family":"Chida","sequence":"first","affiliation":[{"name":"Second Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7020-7312","authenticated-orcid":false,"given":"Masahiko","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3795-4604","authenticated-orcid":false,"given":"Kazumasa","family":"Sekihara","sequence":"additional","affiliation":[{"name":"Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1 Chome-3-2 Kagamiyama, Higashihiroshima 734-8553, Hiroshima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4690-8706","authenticated-orcid":false,"given":"Kazuyoshi","family":"Ohta","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Shimada General Medical Center, 1200-5 Noda, Shimada 427-8501, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gou","family":"Murohisa","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu 430-8558, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fujito","family":"Kageyama","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Hamamatsu Medical Center, 328 Tomitsuka, Hamamatsu 432-8580, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzo","family":"Sasada","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Iwata City Hospital, 512-3 Okubo, Iwata 438-8550, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuki","family":"Oyaizu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Shizuoka City Shizuoka Hospital, 10-93 Otemachi, Shizuoka 420-8630, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Tsugiki","sequence":"additional","affiliation":[{"name":"Minoru Medical Clinic, Mishima 1784-1, Hamamatsu 430-0853, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsutoshi","family":"Tamakoshi","sequence":"additional","affiliation":[{"name":"Tamakoshi Clinic, Maruzuka 262-1, Hamamatsu 435-0046, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomi","family":"Okubo","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai 270-1694, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiyo","family":"Yoshio","sequence":"additional","affiliation":[{"name":"The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3374-7111","authenticated-orcid":false,"given":"Masanori","family":"Atsukawa","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Tokyo 113-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6860-0326","authenticated-orcid":false,"given":"Akihito","family":"Tsubota","sequence":"additional","affiliation":[{"name":"Project Research Units, Research Center for Medical Science, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Tokyo 105-8461, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2473-6966","authenticated-orcid":false,"given":"Yasuhito","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8555, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Kanto","sequence":"additional","affiliation":[{"name":"The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6888-0698","authenticated-orcid":false,"given":"Toshiyuki","family":"Ojima","sequence":"additional","affiliation":[{"name":"Department of Community Health and Preventive Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4986-8578","authenticated-orcid":false,"given":"Kazuhito","family":"Kawata","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Suda","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3754-789X","authenticated-orcid":false,"given":"Tetsuro","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Shizuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality 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