Serum triglyceride and apolipoprotein A1 as dynamic biomarkers in extranodal NK/T-cell lymphoma (ENKTL): A multicenter retrospective and prospective validation study.

Extranodal NK/T-cell lymphoma (ENKTL), an aggressive non-Hodgkin lymphoma subtype, exhibits understudied links between lipid metabolism and clinical outcomes. We analyzed 1,017 patients newly diagnosed with ENKTL and matched controls, with longitudinal LC-MS-based metabolomic profiling (n = 29) and pretreatment tumor transcriptomic analysis (n = 65). Multivariable Cox models evaluated lipid biomarkers. Patients with ENKTL showed significantly elevated triglycerides (TG) and reduced apolipoprotein A1 (ApoA1) vs. controls (both p < 0.001). Elevated TG (progression-free survival [PFS] HR = 1.33, 95% CI 1.04-1.69; overall survival [OS] HR = 1.37, 95% CI 1.04-1.80) and reduced ApoA1 (PFS HR = 1.47, 95% CI 1.07-2.03; OS HR = 1.65, 95% CI 1.15-2.38) independently predicted inferior survival (all p < 0.05). Patients with an objective response demonstrated metabolic profile normalization: patients with high-TG levels (≥ median) experienced TG reduction and patients with low-ApoA1 levels (< median) experienced ApoA1 elevation (both p < 0.001), whereas patients with stable or progressive disease retained baseline profiles. These metabolic shifts predicted survival benefit (all p < 0.001). In the prospective cohort, patients with complete response (CR) had significantly higher baseline levels of 22 serum TG species compared with non-CR patients (fold change > 2.0, p < 0.05). Longitudinal analyses revealed divergent TG trajectories: patients without CR exhibited sustained high-level fluctuations, whereas patients with CR demonstrated stabilization at low levels. Transcriptome analysis suggested tumor-intrinsic lipid dysregulation in patients with high-TG/low-ApoA1 levels. Serum TG and ApoA1 serve as dynamic biomarkers in ENKTL.