Objective <p>Utilizing bioinformatics technology, we aim to screen for differentially expressed genes associated with ferroptosis in lung adenocarcinoma, aiming to identify ferroptosis-related genes that significantly impact the prognosis and immune evasion of this malignancy.</p> Methods <p>RNA-seq data from TCGA and GEO repositories, along with clinical information pertaining to lung adenocarcinoma (LUAD), were compiled and subjected to rigorous analysis to identify differentially expressed genes linked to ferroptosis. Additionally, we examined the prognostic significance of these genes. Concurrently, the correlation between ferroptosis-related genes and immune evasion was scrutinized using the TIDE built-in dataset, resulting in the identification of hub genes. Subsequently, TCGA sequencing data were utilized to delve into the regulatory mechanisms of ferroptosis genes. Finally, to gain further insights, cell experiments were conducted to investigate the alterations in biological functions of LUAD cells following the knockdown of the promising ferroptosis gene, HSPA5.</p> Results <p>The expression of ACSL4 was low in tumor tissues, while DPP4, HSPA5 and HSPB1 were high in tumor tissues. Ferroptosis-related genes HSPA5, GLS2, CDKN1A, FANCD2, SLC7A11, SLC1A5, CARS1, ALOX15, RPL8 associated with prognosis of lung adenocarcinoma. Ferroptosis gene HSPA5 is regulated by transcription factor and ceRNA network to reduce the efficacy of immunotherapy in LUAD. Knockdown of HSPA5 can induce apoptosis of LUAD cells.</p> Conclusion <p>The ferroptosis-related gene HSPA5 diminishes the effectiveness of LUAD immunotherapy by promoting immune evasion, thus serving as a potential indicator for predicting the therapeutic response. Notably, patients with lower HSPA5 expression tend to have a more favorable prognosis. Our discoveries may contribute significantly to the advancement of personalized treatment strategies and the enhancement of immunotherapy outcomes for LUAD patients.</p>