Background Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer. Ferroptosis is a newly recognized process of cell death, which is different from other forms of cell death in morphology, biochemistry, and genetics, and has played a vital role in cancer biology. This study aimed to identify a ferroptosis-related gene signature associated with LUAD prognosis. Methods Dataset TCGA-LUAD which came from the TCGA portal was taken as the training cohort. GSE72094 and GSE68465 from the GEO database were treated as validation cohorts. Two hundred fifty-nine ferroptosis-related genes were retrieved from the FerrDb database. In the training cohort, Kaplan-Meier and univariate Cox analyses were conducted for preliminary screening of ferroptosis-related genes with potential prognostic capacity. These genes then entered into the LASSO Cox regression model, constructing a gene signature. The latter was then evaluated in the training and validation cohorts via Kaplan-Meier, Cox, and ROC analyses. In addition, the correlations between risk score and autophagy were examined by Pearson correlation coefficient. The analyses of GSEA and immune infiltrating were performed for better studying the function annotation of the gene signature and the character of each kind of immune cells played in the tumor microenvironment. Results A 15-gene signature was found from the training cohort and validated by Kaplan-Meier and Cox regression analyses, revealing its independent prognosis value in LUAD. Moreover, the ROC analysis was conducted, confirming a strong predictive ability that this signature owned for LUAD prognosis. One hundred fifty-one of 222 (68.01%) autophagy-related genes were discovered significantly correlated with risk scores. Analyses of GSEA and immune infiltration exhibited in detail the specific pathways that associate with the 15-gene signature and identified the crucial roles of resting mast cells and resting dendritic cells owned in the prognosis of the 15-gene signature. Conclusion In this present study, a novel ferroptosis-related 15-gene signature (RELA, ACSL3, YWHAE, EIF2S1, CISD1, DDIT4, RRM2, PANX1, TLR4, ARNTL, LPIN1, HERPUD1, NCOA4, PEBP1, and GLS2) was built. It could accurately predict the prognosis of LUAD and was related to resting mast cells and resting dendritic cells, which provide potential for the personalized outcome prediction and the development of new therapies in LUAD population.
