Zelkowska_2025_Biomed.Pharmacother_188_118184

Eicosanoids are lipid mediators derived from arachidonic acid that play crucial roles in inflammation, homeostasis, and cancer biology. Distinct enzymes produce them in a cell- and context-dependent manner. We previously reported altered arachidonic acid levels in plasma from non-small cell lung cancer (NSCLC) patients from the Polish Molecular Biomarkers for Individualized Therapy (MOBIT) study. Based upon these findings, we investigated the role of cyclooxygenase (COX) and lipoxygenase (LOX) eicosanoid products in lung cancer. We quantified urinary eicosanoids in 357 NSCLC patients and 119 controls using LC-MS/MS to explore their relevance to lung cancer. The targeted panel included 24 metabolites: 19 eicosanoids, 2 soluble epoxide hydrolase (sEH)-derived linoleic acid products, 2 steroid hormones, and 1 COX inhibitor. The NSCLC cohort was stratified into 148 adenocarcinoma (ADC) and 162 squamous cell carcinoma (SCC) cases, with 202 early-stage (TNM IA-IIB) and 64 advanced-stage (TNM IIIA-IV) patients. Grading further classified the cohort into 13 G1, 82 G2, and 82 G3 cases. Four eicosanoids were significantly elevated in NSCLC patients. TetranorPGJM (1.49-fold, p-value<0.0001) and 11-dehydro-TXB(2) (1.46-fold, p-value<0.0001) were elevated across the cohort, while tetranorPGEM (2.31-fold, p-value<0.0001) and tetranorPGE(1) (1.84-fold, p-value=0.0016) showed increases only in females, highlighting sex-specific differences in PGE(2) metabolism and COX activity. Elevated tetranorPGJM and 11-dehydro-TXB(2) indicated mast cell and platelet activation. Levels of LOX-derived LTE(4) differentiated early- and advanced-stage disease and were elevated in advanced NSCLC (1.06-fold, p-value=0.0370). These findings reveal systemic dysregulation of COX- and LOX-derived eicosanoids in NSCLC, linked to sex and immune cell activation.