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Background: Esophageal cancer, particularly esophageal squamous cell carcinoma (ESCC), is a leading cause of cancer-related death and has a poor prognosis. Despite the advancements in multidisciplinary therapies, resistance to conventional treatments warrants the development of novel therapeutic strategies. Ferroptosis, a form of cell death dependent on intracellular iron, has emerged as a potential mechanism for targeting cancer cells resistant to apoptosis. Guanosine triphosphate cyclohydrolase 1 (GCH1) has been identified as a novel antagonist of ferroptosis; however, its role in ESCC remains unclear. This study aimed to investigate the correlation between the expression and accumulation of the lipid peroxidation markers and regulators, including GCH1, in patients with ESCC and examined their prognostic significance. Furthermore, we investigated the relationship between lipid peroxidation regulators and cell death using an in vitro system to establish the basis for new therapeutic strategies. Methods: We retrospectively analyzed 312 patients with ESCC who underwent radical esophagectomy at the Tokyo Medical and Dental University. Immunohistochemistry was performed to evaluate the expression of lipid peroxidation markers (4-hydroxy-2-nonenal) and regulators (glutathione peroxidase 4 [GPX4], ferroptosis suppressor protein 1 [FSP1], and GCH1). The correlation between these markers, clinicopathological features, and overall survival was assessed. In vitro experiments were performed using KYSE-150 cells to investigate the effects of GCH1 knockdown and overexpression on cell proliferation, cisplatin-induced cell death, and ferroptosis. Results: Low GCH1 expression was significantly associated with a poor prognosis in patients with ESCC. GCH1 expression correlated with lymph node metastases, vessel invasion, and the pathological tumor stage. In vitro , GCH1-knockdown cells exhibited increased proliferation and resistance to cisplatin-induced cell death, whereas GCH1 overexpression reduced cell proliferation. Simultaneous inhibition of GPX4 and FSP1 induced mild cell death; however, GCH1 knockdown dramatically enhanced ferroptosis, suggesting a synergistic effect. Conclusion: GCH1 is a critical prognostic factor for ESCC and plays a significant role in the regulation of cell proliferation and ferroptosis. Targeting GCH1 in combination with GPX4 and FSP1 inhibitors may offer a novel therapeutic strategy for overcoming resistance in ESCC. Further studies are warranted to elucidate the involved molecular mechanisms and validate these findings in vivo. [ABSTRACT FROM AUTHOR]

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]