The alteration of the metabolomic profile in lung cancer represents one of the hallmarks for tumor cells which opportunistically hijack the physiological pathways in favor of carcinogenesis. In our previous study, we found circulating and tumor-associated caspase-4 as a novel diagnostic, predictive and prognostic biomarker for non-small cell lung cancer (NSCLC) patients. According to the altered metabotype of lung cancer patients, the main goal of the actual study was to understand any correlation between caspase-4 and the metabolomic profile of NSCLC patients (n=104, 60±10 (mean±S.E.M) years of age), stratified as caspase-4 positive or negative. Metabolomic profiles have been obtained by using gas chromatography coupled to mass spectrometry (GC-MS analysis), carried out on both lung tumor tissues and plasma. We found that circulating caspase-4 was correlated to lactate dehydrogenase (LDH), in that 82.69% of caspase-4 positive patients (86 out of 104) had high plasma levels of LDH, widely recognized as a marker associated to tumor progression and poor prognosis, compared to healthy subjects (n=61) (p<0,0001; according to Two-tailed Mann Whitney U test). However, this effect was not observed in caspase-4 positive tumor tissues, where instead, fatty acid biosynthesis was favoured in that the malonic acid and the palmitic acid were higher than in non-cancerous (p<0,0001 and p=0,0009, respectively, according to One-Way ANOVA followed by Dunn’s multiple comparison post-test) and caspase-4 negative tissues (p=0,042 and p=0,0215 respectively, according to One-Way ANOVA followed by Dunn’s multiple comparison post-test). Moreover, caspase-4 positive tumor tissues had significantly higher levels of transaldolase (p=0,0007, according to Two-tailed Mann Whitney U test), pyruvate kinase (p=0,002, according to Two-tailed Mann Whitney U test) and fatty acid-binding protein (p=0,0108, according to Two-tailed Mann Whitney U test). Instead, malate dehydrogenase and phosphoglycerate kinase tended to decrease in tumor tissues, implying that higher consumption of glucose occurred. On the other hand, dysregulated glucose metabolism was counterbalanced by a higher presence of succinate dehydrogenase (SDHA) (p=0,0381, according to Two-tailed Mann Whitney U test) and by the gluconeogenic valine which supported the Krebs’ cycle. In conclusion, we found that the recently identified caspase-4 positive subpopulation of NSCLC patients is characterized by an altered lipidomic profile accompanied by alternative pathways to guarantee glucose metabolism. This shifted equilibrium in favor of fatty acid biosynthesis, was balanced by the anaerobic LDH activity and valine/proline/SDHA-supported Krebs’ cycle in order to provide ATP to the tumor cells allowing them to survive and proliferate.