Non-Specific Elevated Serum Free Fatty Acids in Lung Cancer Patients: Nutritional or Pathological?

Abstract

Importance: The reprogramming of lipid metabolism is a significant feature of tumors, yet the circulating levels of fatty acids in lung cancer patients remain to be explored. Moreover, the association between fatty acid levels and related factors, including nutritional intake, tumor metabolism, and tumor immunity, has been rarely discussed. Objectives: To explore the differences in serum free fatty acids between lung cancer patients and healthy controls, and investigate the factors associated with this phenomenon. Design and participants: A case-control study enrolled 430 primary lung cancer patients and 430 healthy controls. The whole population had a medium [Q1, Q3] age of 48.0 [37.0, 58.9] years, with females comprising 56% of the participants. The absolute quantification of 27 serum free fatty acids (FFAs) was measured using a liquid chromatography–mass spectrometry (LC-MS/MS) detection. Data, including dietary intake, blood indicators, and gene expression of lung tissues, were obtained from questionnaires, blood tests, and RNA-sequencing. Statistical differences in FFA levels between lung cancer patients and healthy controls were investigated, and related contributing factors were explored. Results: Levels of 22 FFAs were significantly higher in lung cancer patients compared to those in healthy controls, with fold changes ranging from 1.14 to 1.69. Lung cancer diagnosis models built with clinical and FFA features yielded an area under the receiver operating characteristic curve (AUROC) of 0.830 (0.780–0.880). Total fatty acids (TFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) showed no significant dietary–serum associations, indicating that the elevations might not be attributed to an excessive intake of relevant fatty acids from the diet. For RNA-sequencing of lung tissues, among the 68 lipid metabolism genes, 26 genes showed significant upregulation (FDR < 0.05), while 33 genes exhibited significant downregulation, indicating the involvement of the fatty acids in the tumor metabolism. Through joint analysis with immune cells and inflammatory factors in the blood, fatty acids might exert suppressing effects on tumor immunity. Conclusions: Lung cancer patients had elevated levels of serum free fatty acids compared to healthy individuals. The elevations might not be attributed to an excessive intake of relevant fatty acids from the diet but related to pathological factors of tumor metabolism and immunity. These findings will complement research on fatty acid metabolism of lung cancer and provide insights into potential intervention targets.