Work

Plasma Metabolomic Profiling in Essential Thrombocythemia: Pathway-Level Alterations and Their Relationship to Treatment Status, Platelet Count, and JAK2V617F Status

Year: 2026

Type: article

Abstract: Background/Objectives: Essential thrombocythemia (ET) is a JAK-STAT-driven myeloproliferative neoplasm with an incompletely defined metabolic phenotype. This study aimed to characterize the plasma metabolome of ET and to determine whether it differs according to JAK2V617F status, platelet count (≥450 vs. <450 × 109/L), and cytoreductive treatment. Methods: Untargeted plasma metabolomic profiling by liquid chromatography-mass spectrometry (LC-MS) was performed in 70 ET patients and 47 healthy controls. Multivariate analysis used principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) validated by nested cross-validation and permutation testing. Differentially abundant metabolites were defined by fold-change (FC > 1.5 or <0.67) and a Benjamini–Hochberg false discovery rate (q) below 0.05; identifications were annotated at Level 1 (retention time-matched authentic standards) or Level 3 (molecular formula), and pathways were examined by over-representation analysis in Reactome. Results: PCA and PLS-DA separated ET from controls (PLS-DA R2Y = 0.96; nested cross-validation Q2 = 0.91; permutation p = 0.001). Nineteen metabolites met the criteria: seven Level 1 identifications (succinate, an aminobutyrate isomer, uridine and N-acetylphenylalanine higher; proline, glucuronolactone and quinaldate lower in ET) and twelve Level 3 candidates dominated by platelet-derived eicosanoids, including 11-dehydro-thromboxane B2 (detected in 26% of controls and 99% of patients) and thromboxane B2 (4% and 84%), prostaglandin D2/E2 and B1/A1 isomers, a hydroxy-docosahexaenoic acid isomer, and corticosteroid intermediates. Reactome over-representation analysis, which rests mainly on Level 3 candidates, ranked synthesis of prostaglandins and thromboxanes and arachidonate metabolism highest (FDR 7 × 10−5), followed by fatty acid metabolism, pyrimidine catabolism and, on the basis of Level 3 candidates only, mineralocorticoid biosynthesis. The signature was similar in direction across cytoreductive-therapy, platelet-count and JAK2V617F strata. Conclusions: These exploratory data describe a plasma metabolite signature of aspirin-treated ET dominated by platelet-derived eicosanoids, together with changes in succinate and pyrimidine-related metabolites and candidate changes in corticosteroid intermediates; because aspirin exposure and disease status were fully confounded, the signature requires confirmation with targeted methods in independent cohorts.

Source: Metabolites

DOI: 10.3390/metabo16110809