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Updated: Mar 1, 2026
Development of Compendium for Esophageal Squamous Cell Carcinoma
Published on: April 12, 2024
Roles of GPX4 and FSP1 in Esophageal Squamous Cell Carcinoma Treated With Neoadjuvant Chemotherapy
Tomohiro Takahashi1, Yuji Shishido2, Tomohiko Sakabe3
1Division of Gastrointestinal and Pediatric Surgery, Department of Surgery, School of Medicine, Faculty of Medicine, Tottori University, Yonago, Japan; totakahashi@tottori-u.ac.jp.
Background/Aim:
Esophageal squamous cell carcinoma (ESCC) has a poor prognosis owing to chemoresistance to neoadjuvant chemotherapy (NAC). Ferroptosis, regulated by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), is a potential therapeutic target. This study investigated the significance of GPX4 and FSP1 in NAC-treated ESCC.
Patients And Methods:
We analyzed 97 patients with ESCC who underwent NAC and esophagectomy. GPX4 and FSP1 expressions were assessed in relation to clinicopathological factors and survival. Three ESCC cell lines were exposed to cisplatin or 5-fluorouracil with or without the ferroptosis inhibitor liproxstatin-1, GPX4 inhibitor RSL3, or FSP1 inhibitor iFSP1. Cell viability, mRNA expression, and drug interactions were evaluated.
Results:
Post-NAC GPX4-positivity (44.3%) was associated with aggressive clinicopathological features, poor histopathological effect, and worse overall and relapse-free survival. Post-NAC FSP1-positivity (28.9%) was associated with poor histopathological effects. Persistent GPX4-positivity from pre- to post-NAC was an independent prognostic factor for poor relapse-free survival (hazard ratio=2.098; 95% confidence interval=1.013-4.345). Cisplatin up-regulated GPX4 mRNA expression, particularly in KYSE70 cells. Liproxstatin-1 partially attenuated chemotherapy-induced cytotoxicity without altering the half-maximal inhibitory concentration. RSL3 enhanced cisplatin and 5-fluorouracil effects in a cell line-dependent manner.
Conclusion:
GPX4 mediates tumor aggressiveness and chemoresistance in NAC-treated ESCC. Persistent GPX4-positivity may serve as a prognostic biomarker, and targeting the GPX4-mediated ferroptosis pathway with standard chemotherapy may overcome resistance in advanced ESCC.
