<p>Cancer cells exhibit metabolic reprogramming to fulfill their increased demands for abnormal growth and proliferation. We studied metabolic profiles of squamous cell lung carcinoma (LUSC).</p><p>Elevated arginine levels and reduced acylcarnitine C18:2, along with decreased phosphatidylcholine (PC) with acyl-alkyl residues C38:0 were associated with the diagnosis and prognosis of LUSC. Most of the PCs demonstrated a decrease, while lysophosphatidylcholines (LPC) exhibited an increase in LUSC patients. Network analysis unveiled that LPCs mediated PC and amino acids subgroup in LUSC compared to the control group. Analysis of public LUSC data confirmed associations between the expression levels of genes encoding enzymes involved in the biosynthesis pathways of arginine, proline (<i>ASL</i>,<i> OTC</i>,<i> PYCR2</i>), PC (<i>CEPT1</i>,<i> CHPT1</i>,<i> LPCAT1</i>) and LPC (<i>LCAT</i>,<i> PLA2G16</i>,<i> PLB1</i>) with a 5-yr survival outcome. The observed metabolic reprogramming in LUSC patients suggested the potential utility of metabolites as a supportive biomarkers for LUSC diagnosis.</p>