Stage-dependent metabolic reprogramming in treatment-naïve lung adenocarcinoma: From oxidative flexibility to glycolytic entrapment.

Abstract

e20566 Background: Lung adenocarcinoma demonstrates metabolic reprogramming during progression, frequently shifting from mitochondrial oxidative phosphorylation (OXPHOS) toward aerobic glycolysis (Warburg phenotype). We evaluated stage-associated systemic metabolic, inflammatory, and oxidative stress signatures in treatment-naïve patients. Methods: In a prospective cohort, 150 patients with histologically confirmed lung adenocarcinoma were analyzed: stage IV (n = 75) versus early stage I–II (n = 75). Fasting plasma and 24-hour urine were collected. Glycolysis markers (glucose, lactate, pyruvate), OXPHOS-associated metabolites (β-hydroxybutyrate, acetoacetate, glutamine, alanine), cytokines (IL-6, IL-1β, TNF-α), oxidative stress–related markers (melatonin, dopamine), and LDH isoenzymes (LDH-1 to LDH-5) were assessed using enzymatic assays, HPLC/GC-MS, ELISA, and electrophoresis. Group comparisons used ANOVA; significance threshold p < 0.05. Results: Compared with stage I–II, stage IV disease showed significantly increased glycolysis markers (relative levels): glucose 160 vs 100, lactate 150 vs 80, and pyruvate 130 vs 70 (all p < 0.01). OXPHOS-associated metabolites were reduced: β-hydroxybutyrate 40 vs 100, acetoacetate 50 vs 95, glutamine 45 vs 90, and alanine 35 vs 85 (all p < 0.01). Pro-inflammatory cytokines were elevated in stage IV: IL-6 80 vs 30, IL-1β 70 vs 25, and TNF-α 65 vs 20 (all p < 0.01). LDH-5 increased (80 vs 25; p < 0.01), consistent with enhanced glycolytic flux. Oxidative stress–related markers decreased: melatonin 35 vs 90 and dopamine 40 vs 85 (both p < 0.01). Conclusions: Advanced (stage IV) lung adenocarcinoma is characterized by a systemic pattern consistent with “glycolytic entrapment,” accompanied by inflammatory cytokine elevation, LDH-5 upregulation, and depletion of OXPHOS-linked metabolites and antioxidant markers. These findings support stage-informed biomarker strategies and provide a rationale for therapeutically targeting the glycolysis–lactate axis and inflammatory pathways in advanced disease.