12-Hydroxyheptadecatrienoic Acid Predicts Hepatocellular Carcinoma Development During Nucleos(t)ide Analogue Therapy
by
, , , , ,
Hiroko Ikenaga
1
,
Ritsuzo Kozuka
1,
Kirara Inoue
1,2,
Tsutomu Matsubara
3,
Naoshi Odagiri
1,
Kanako Yoshida
1,
Kohei Kotani
1,
Etsushi Kawamura
1,
Atsushi Hagihara
1,
Hideki Fujii
1,
Masaru Enomoto
1,* and 
Sawako Uchida-Kobayashi
1 1
Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
2
Department of Biology, Graduate School of Science, Osaka Metropolitan University, Osaka 558-8585, Japan
3
Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
*
Author to whom correspondence should be addressed.
Cancers 2026, 18(4), 542; https://doi.org/10.3390/cancers18040542
Submission received: 1 January 2026
/
Revised: 4 February 2026
/
Accepted: 5 February 2026
/
Published: 7 February 2026
(This article belongs to the Collection Primary Liver Cancer)
Simple Summary
Even with long-term antiviral therapy for chronic hepatitis B, some patients still develop liver cancer. We investigated whether polyunsaturated fatty acid metabolites—bioactive lipids involved in inflammation and other processes—could predict this risk before antiviral treatment begins. We measured 158 of these metabolites in pre-treatment blood samples from 195 patients starting nucleos(t)ide analogue therapy and followed them. Low levels of 12-hydroxyheptadecatrienoic acid (12-HHT) were strongly linked to liver cancer development. Patients with low 12-HHT had a 4.28-fold higher risk of liver cancer development than those with higher levels. Prediction improved further when 12-HHT was combined with the fibrosis-4 (FIB-4) index, a routine measure of liver scarring. Over 10 years of follow-up, about two-thirds of patients with both high FIB-4 and low 12-HHT developed liver cancer compared with about 1% of those with low FIB-4 and high 12-HHT. If confirmed, this marker could support personalised surveillance and help target prevention during long-term antiviral therapy.
Abstract
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-naïve patients who received NUC therapy. Associations between metabolic factors—especially PUFA metabolites—and 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 ≤ 3.82 ng/mL compared with 3.3% at both time points in those with 12-HHT concentration > 3.82 ng/mL (p < 0.001). In multivariate analysis, low 12-HHT concentration (≤3.82 ng/mL; p = 0.027; hazard ratio [HR], 4.28; 95% confidence interval [CI], 1.18–15.55) and a fibrosis-4 index ≥ 4.08 (p = 0.005; HR, 5.19; 95% CI, 1.64–16.41) 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.
