Researchers performed untargeted metabolomics on plasma samples from the 60 participants to identify molecular differences between pancreatic cancer cases and controls. Differential metabolites were identified using orthogonal partial least-squares discriminant analysis, with thresholds of a variable importance in projection score above 1, a fold change greater than 2 or below 0.5, and an adjusted P value below 0.05. Thirty-four plasma metabolites significantly distinguished the groups, and the altered metabolites were primarily enriched in the arginine biosynthesis pathway.

The team next used multivariate ROC analysis with internal validation to prioritize potential diagnostic biomarkers. The five metabolites with the highest variable importance in projection scores were 4-oxoproline, 1,4-dimethylpiperazine, pyridoxamine, urocanic acid and L-cysteine-S-sulfate. Their analysis placed particular emphasis on 1,4-dimethylpiperazine because its diagnostic performance was similar to that of CA19-9 in this cohort and no significant relationship was found with the assessed liver-function parameters or C-reactive protein, or CRP.

Those associations were evaluated through Spearman correlation and multiple linear regression analyses. CA19-9 showed a positive correlation with gamma-glutamyl transferase, or GGT, with a correlation coefficient of 0.364. By contrast, 1,4-dimethylpiperazine was not significantly associated with liver-function parameters or CRP. The reported null association applies only to the measures and participants included in this study and does not establish that the metabolite is free from liver or inflammatory influences in other populations.

Combining 1,4-dimethylpiperazine with CA19-9 increased the AUC to 0.982. This combined value was significantly higher than the AUC for 1,4-dimethylpiperazine alone, which was 0.893 (P = 0.035). It did not, however, significantly outperform CA19-9 alone, for which the AUC was 0.904; the comparison between the combination and CA19-9 yielded P = 0.076. Thus, the study provides statistical evidence of added performance relative to the metabolite by itself, but not of a significant advantage over CA19-9 by itself.

OPLS-DA also separated the pancreatic cancer group into two subclusters that differed in alkaline phosphatase levels and smoking history. This observation indicates heterogeneity within the cancer cases included in the exploratory cohort. It also matters for interpreting the diagnostic results: the reported AUC values came from a selected sample of 30 pancreatic cancer patients and 30 healthy controls, with internal validation rather than assessment in a larger, independently validated cohort.

Pancreatic cancer is an aggressive malignancy, and the study reports a five-year survival rate below 10%. CA19-9 is the most commonly used serum biomarker for pancreatic cancer diagnosis, but the investigators noted that cholestasis and inflammation can influence it. The study therefore examined whether plasma metabolites could identify pancreatic cancer without the significant associations with liver function or inflammation detected for 1,4-dimethylpiperazine in this cohort. The findings do not establish improved early detection, replacement of CA19-9, or better patient outcomes.

The authors characterized 1,4-dimethylpiperazine as a promising complementary biomarker and called for validation in larger, disease-controlled cohorts. Within the 60-person study, its AUC was similar to that of CA19-9, its combination with CA19-9 significantly improved performance over 1,4-dimethylpiperazine alone, and no significant association was detected with the liver-function and inflammatory measures evaluated. These exploratory results support further evaluation, while the small sample and internally validated analysis limit how broadly the findings can be applied.

Subject of Research: Exploratory evaluation of 1,4-dimethylpiperazine as a plasma diagnostic biomarker for pancreatic cancer.

Article Title: Plasma metabolite 1,4-dimethylpiperazine: a valuable diagnostic biomarker with no significant association with liver function or inflammation

Article References: Wang, X., Sun, H., Yang, T., Liu, W., Yang, H., Zhang, J., Yu, D., Wang, M., Xu, J., Shan, Z., Qiu, X., Wang, C., & Li, M. (2026). Plasma metabolite 1,4-dimethylpiperazine: a valuable diagnostic biomarker with no significant association with liver function or inflammation. BMC Cancer. https://doi.org/10.1186/s12885-026-17015-w

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17015-w

Keywords: pancreatic cancer, 1,4-dimethylpiperazine, plasma metabolomics, CA19-9, diagnostic biomarkers, liver function, inflammation, ROC analysis, Plasma, metabolite, dimethylpiperazine, valuable