This study investigates the role of NEAT1_1 in gefitinib resistance in lung adenocarcinoma (LUAD) through its regulation of AKR1C1-mediated ferroptosis defense. Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is widely used for treating advanced LUAD with EGFR mutations. However, drug resistance significantly limits its clinical effectiveness. The study reveals that gefitinib resistance in LUAD cells is partially due to the induction of ferroptosis, a type of regulated cell death. Ferroptosis protection, particularly through the upregulation of AKR1C1, contributes to gefitinib resistance. AKR1C1, an aldo-keto reductase family member, suppresses ferroptosis by detoxifying lipid peroxides. The study shows that AKR1C1 is significantly upregulated in gefitinib-resistant LUAD cells and is associated with poor prognosis in patients receiving first-generation EGFR-TKIs. Knockdown of AKR1C1 partially reverses gefitinib resistance by sensitizing LUAD cells to gefitinib-mediated ferroptosis. The expression of AKR1C1 is upregulated in gefitinib-resistant LUAD cells due to the decreased expression of miR-338-3p. NEAT1_1, a long non-coding RNA, sponges miR-338-3p, neutralizing its suppression on AKR1C1. The NEAT1_1/miR-338-3p/AKR1C1 axis promotes gefitinib resistance, proliferation, migration, and invasion in LUAD cells. The study highlights the role of the NEAT1_1/miR-338-3p/AKR1C1 axis in gefitinib resistance and suggests that targeting this axis could be a novel strategy for overcoming gefitinib resistance in LUAD patients with EGFR mutations. The findings provide insights into the molecular mechanisms underlying gefitinib resistance and offer potential therapeutic targets for improving clinical outcomes in LUAD patients.This study investigates the role of NEAT1_1 in gefitinib resistance in lung adenocarcinoma (LUAD) through its regulation of AKR1C1-mediated ferroptosis defense. Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is widely used for treating advanced LUAD with EGFR mutations. However, drug resistance significantly limits its clinical effectiveness. The study reveals that gefitinib resistance in LUAD cells is partially due to the induction of ferroptosis, a type of regulated cell death. Ferroptosis protection, particularly through the upregulation of AKR1C1, contributes to gefitinib resistance. AKR1C1, an aldo-keto reductase family member, suppresses ferroptosis by detoxifying lipid peroxides. The study shows that AKR1C1 is significantly upregulated in gefitinib-resistant LUAD cells and is associated with poor prognosis in patients receiving first-generation EGFR-TKIs. Knockdown of AKR1C1 partially reverses gefitinib resistance by sensitizing LUAD cells to gefitinib-mediated ferroptosis. The expression of AKR1C1 is upregulated in gefitinib-resistant LUAD cells due to the decreased expression of miR-338-3p. NEAT1_1, a long non-coding RNA, sponges miR-338-3p, neutralizing its suppression on AKR1C1. The NEAT1_1/miR-338-3p/AKR1C1 axis promotes gefitinib resistance, proliferation, migration, and invasion in LUAD cells. The study highlights the role of the NEAT1_1/miR-338-3p/AKR1C1 axis in gefitinib resistance and suggests that targeting this axis could be a novel strategy for overcoming gefitinib resistance in LUAD patients with EGFR mutations. The findings provide insights into the molecular mechanisms underlying gefitinib resistance and offer potential therapeutic targets for improving clinical outcomes in LUAD patients.