Identification and Validation of the Ferroptosis‐Related Gene SLC2A1 as a Novel Prognostic Biomarker for Osimertinib Resistance in LUAD

Introduction Osimertinib shows remarkable efficacy as a first‐line therapy for lung adenocarcinoma (LUAD), yet acquired resistance remains a major challenge. Ferroptosis dysregulation has emerged as a key contributor to drug resistance, highlighting ferroptosis‐associated genes as potential biomarkers and therapeutic targets. Methods Ferroptosis‐related osimertinib resistance genes were identified through integrated TCGA and GEO analyses, and a prognostic model was constructed using Cox and LASSO regression. Drug‐response profiles, immune infiltration patterns, and clinical associations were systematically evaluated. Functional experiments were conducted to elucidate the role of SLC2A1 in osimertinib resistance. Results A three‐gene ferroptosis‐associated signature (SLC2A1, LIFR, and GDF15) was established with high prognostic accuracy and independence. Low‐risk patients showed greater chemotherapy sensitivity, whereas high‐risk patients exhibited increased M0/M1 macrophage and CD8 + T‐cell infiltration. High SLC2A1 expression was associated with reduced infiltration of antitumor lymphocytes—including naïve CD8 + T cells, Th17, Tfh, MAIT cells, B cells, γδT cells, and CD4 + /CD8 + T cells—and increased levels of exhausted T cells, regulatory T cells, Th1/Tem cells, and myeloid‐derived populations (DCs, monocytes, macrophages, and neutrophils). Clinical cohort validation confirmed the prognostic relevance of these genes. Mechanistically, SLC2A1 enhanced osimertinib resistance by activating the SLC7A11/GPX4 antioxidant axis and suppressing lipid peroxidation, thereby promoting ferroptosis evasion and reshaping an immunosuppressive tumor microenvironment. Conclusion This study reveals the clinical and biological significance of ferroptosis‐related resistance genes in LUAD and identifies a previously unrecognized mechanism through which SLC2A1 drives osimertinib resistance by promoting ferroptosis escape and reshaping the immunosuppressive tumor microenvironment. These findings highlight SLC2A1 as a promising therapeutic target for overcoming resistance and improving precision treatment strategies in LUAD.