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

Simple Summary: This study was proposed to address the poor prognosis of primary lung cancer, particularly lung adenocarcinoma, which remains a leading cause of cancer-related mortality. The authors aim to explore the prognostic impact of lipid peroxidation markers and regulators involved in ferroptosis, an emerging form of cell death, to identify potential therapeutic targets. By analyzing the expression levels of glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and 4-Hydroxy-2-nonenal (4-HNE) in resected lung adenocarcinoma tissues, the study seeks to establish a relationship with clinicopathological factors and patient outcomes. The findings revealed that low 4-HNE and low GPX4 expression are associated with worse prognosis, while low FSP1 expression correlates with unfavorable relapse-free survival. These insights suggest that lipid peroxidation markers and ferroptosis regulators could serve as valuable prognostic biomarkers and therapeutic targets. This research has the potential to significantly impact the scientific community by guiding the development of novel, targeted therapies for lung adenocarcinoma, ultimately improving patient outcomes. Background: 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. Methods: 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. Results: 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. Conclusions: These findings suggest that lipid peroxidation markers and regulators can serve as prognostic biomarkers and therapeutic targets in lung adenocarcinoma. [ABSTRACT FROM AUTHOR]