GPX4 and FSP1 Expression in Lung Adenocarcinoma: Prognostic Implications and Ferroptosis-Based Therapeutic Strategies

<b>Background:</b> Primary lung cancer is among the cancers with the poorest prognosis, having the highest mortality rate among men and the second highest among women in Japan. While surgery is the primary treatment, advanced stages often require pharmacotherapy. Recently, ferroptosis, an iron-dependent form of cell death caused by lipid peroxidation, has gained attention as a potential therapeutic strategy. This study investigated the prognostic impact of lipid peroxidation marker and regulators involved in ferroptosis in lung adenocarcinoma. <b>Methods</b>: We analyzed 207 patients who underwent resection surgery for lung adenocarcinoma at Tokyo Medical and Dental University Hospital. Immunohistochemistry was used to evaluate the expression levels of glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and 4-hydroxy-2-nonenal (4-HNE). The association between these markers and clinicopathological factors was assessed, and in vitro experiments were conducted to examine the effects of these markers on cell death. <b>Results</b>: Low cytoplasmic accumulation of 4-HNE and low expression of GPX4 were associated with a worse prognosis, and low FSP1 expression was associated with unfavorable relapse-free survival. In vitro experiments demonstrated that 4-HNE inhibited cell proliferation, and combined inhibition of GPX4 and FSP1 induced ferroptosis. <b>Conclusions</b>: These findings suggest that lipid peroxidation markers and regulators can serve as prognostic biomarkers and therapeutic targets in lung adenocarcinoma.