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

Background Pancreatic cancer (PC) is an extremely aggressive malignancy with a 5-year survival rate below 10%. Carbohydrate antigen 19-9 (CA19-9), the most commonly used serum biomarker for PC diagnosis, can be influenced by cholestasis and inflammation, highlighting the need for more reliable screening strategies. This study aimed to identify plasma metabolites that may serve as diagnostic biomarkers for PC without significant associations with these confounding factors. Methods Untargeted metabolomics was performed on plasma samples from 30 PC patients and 30 healthy controls (HC). Differentially abundant metabolites were identified by orthogonal partial least-squares-discriminant analysis (OPLS-DA) (VIP > 1, FC > 2 or < 0.5, adjusted P < 0.05). Multivariate ROC analysis with internal validation was conducted to screen for potential biomarkers, and Spearman correlation and multiple linear regression were performed to assess associations with liver function and C-reactive protein (CRP). Results OPLS-DA revealed two distinct PC subclusters differing in ALP levels and smoking history. Thirty-four plasma metabolites significantly distinguished PC from HC and were primarily enriched in the arginine biosynthesis pathway. Multivariate ROC analysis identified 4-oxoproline, 1,4-dimethylpiperazine, pyridoxamine, urocanic acid, and L-cysteine-S-sulfate as the top 5 metabolites ranked by VIP. Correlation and multiple linear regression analyses showed that 1,4-dimethylpiperazine was not significantly associated with liver function parameters or CRP in this cohort, whereas CA19-9 showed a positive correlation with GGT ( r = 0.364). 1,4-Dimethylpiperazine showed diagnostic performance comparable to that of CA19-9 (AUC: 0.893 vs. 0.904, P = 0.860). The combination of 1,4-dimethylpiperazine with CA19-9 significantly improved the AUC compared with 1,4-dimethylpiperazine alone (0.982 vs. 0.893, P = 0.035), but did not significantly outperform CA19-9 alone (0.982 vs. 0.904, P = 0.076). Conclusion 1,4-dimethylpiperazine exhibited diagnostic performance comparable to that of CA19-9 and no significant association with liver function parameters or CRP in this cohort. Its combination with CA19-9 significantly improved diagnostic accuracy compared with 1,4-dimethylpiperazine alone but did not significantly outperform CA19-9 alone. These exploratory findings suggest that 1,4-dimethylpiperazine may be a promising complementary biomarker for PC, warranting validation in larger, disease-controlled cohorts.