Background. The development of lung adenocarcinoma (LUAD) involves the interactions between cell proliferation and death. Autophagy-dependent ferroptosis, a distinctive cell death process was implicated in a multitude of diseases, whereas no research revealing the relationship between autophagy-dependent ferroptosis and LUAD pathogenesis was reported. Thus, the primary objective was to explore the role and potential function of the autophagy-dependent ferroptosis-related genes in LUAD.Methods. Clinical information and transcriptome profiling of patients with LUAD were retrieved and downloaded from open-source databases. Autophagy-dependent ferroptosis-related genes were screened by published articles. The key gene was identified as the intersection between the differentially expressed genes and prognosis-related genes. Patients were divided into high- and low-risk groups using the expression level of the key gene. The validity of the key gene prognosis model was verified by survival analysis. The correlation between the clinical characteristics of LUAD and the expression level of the key gene was analyzed to explore the clinical significance and prognosis value. And the roles of the key gene in response to chemotherapy, immune microenvironment and tumor mutation burden were predicted. The validation of key gene expression levels were further performed by immunohistochemistry staining.Results. FANCD2, a key autophagy-dependent ferroptosis-related gene by searching database, was confirmed as an independent prognostic factor for LUAD occurrence. The high expression level of FANCD2 was associated with an advantaged TNM stage, a less chemotherapy sensitivity, a low ImmuneScore, which indicated a deactivation status in immune microenvironment, a high tumor mutation burden, and a poor survival for LUAD patients. Pathway enrichment analysis showed that FANCD2 were involved in response to oxidative stress and neutrophil mediated immunity. Immunohistochemistry staining showed that the expression level of FANCD2 is higher in LUAD patients than normal tissue samples, which was in accordance with the database report.Conclusion. FANCD2, a key gene related to autophagy-dependent ferroptosis, could work as a biomarker, which predicts the survival, chemotherapy sensitivity, tumor immunity and mutation burden of LUAD. Research of autophagy-dependent ferroptosis and targeting the FANCD2 may offer a new perspective for the treatment and improvement of prognosis in LUAD.