{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T07:24:31Z","timestamp":1770708271607,"version":"3.49.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T00:00:00Z","timestamp":1770422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["JP25K11210"],"award-info":[{"award-number":["JP25K11210"]}]},{"name":"Osaka Cancer Society"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Alterations in polyunsaturated fatty acid (PUFA) metabolites have been linked to the development of hepatocellular carcinoma (HCC). However, the association between PUFA metabolites and HCC development during nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B virus infection remains unclear. Methods: This study enrolled 195 NUC-na\u00efve patients who received NUC therapy. Associations between metabolic factors\u2014especially PUFA metabolites\u2014and HCC development during NUC therapy were evaluated. Baseline serum concentrations of 158 PUFA metabolites were quantified using targeted lipidomic analysis. Results: Nineteen patients developed HCC during the follow-up period. The cumulative incidences of HCC at 5 and 10 years were 7.7% and 12.4%, respectively. Variable importance in projection analysis identified 12-hydroxyheptadecatrienoic acid (12-HHT) as the top-ranked metabolite differentiating patients with and without HCC development. Furthermore, 14 metabolites were significantly associated with HCC development based on the log-rank test with 12-HHT being the most significant predictor. The cumulative incidences of HCC at 5 and 10 years were 13.7% and 24.7%, respectively, in patients with 12-HHT concentration \u2264 3.82 ng\/mL compared with 3.3% at both time points in those with 12-HHT concentration &gt; 3.82 ng\/mL (p &lt; 0.001). In multivariate analysis, low 12-HHT concentration (\u22643.82 ng\/mL; p = 0.027; hazard ratio [HR], 4.28; 95% confidence interval [CI], 1.18\u201315.55) and a fibrosis-4 index \u2265 4.08 (p = 0.005; HR, 5.19; 95% CI, 1.64\u201316.41) were significantly associated with HCC development during NUC therapy. Conclusions: Pre-treatment 12-HHT represents a novel predictive biomarker for HCC development during NUC therapy.<\/jats:p>","DOI":"10.3390\/cancers18040542","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T12:42:42Z","timestamp":1770640962000},"page":"542","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["12-Hydroxyheptadecatrienoic Acid Predicts Hepatocellular Carcinoma Development During Nucleos(t)ide Analogue Therapy"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8952-5353","authenticated-orcid":false,"given":"Hiroko","family":"Ikenaga","sequence":"first","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ritsuzo","family":"Kozuka","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9106-6922","authenticated-orcid":false,"given":"Kirara","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"},{"name":"Department of Biology, Graduate School of Science, Osaka Metropolitan University, Osaka 558-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1100-1052","authenticated-orcid":false,"given":"Tsutomu","family":"Matsubara","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1298-7351","authenticated-orcid":false,"given":"Naoshi","family":"Odagiri","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanako","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohei","family":"Kotani","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9814-0009","authenticated-orcid":false,"given":"Etsushi","family":"Kawamura","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Hagihara","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaru","family":"Enomoto","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sawako","family":"Uchida-Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,7]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2025). 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