Solute carrier family 7 member 11(SLC7A11) is a component of cysteine/glutamate transporter, which plays a key role in tumor growth; however, its underlying effect on radiosensitivity in esophageal squamous cell carcinoma (ESCC) remains unclear. This study aimed to clarify SLC7A11’s expression and correlation with nuclear expression of nuclear factor erythroid-2 (NRF2)-associated radioresistance in ESCC. We included 127 ESCC patients who received radical chemoradiotherapy. Immunohistochemical staining was used to detect SLC7A11 and NRF2 nuclear expression, and the relationship between clinicopathological characteristics and survival rates or therapy response were evaluated. Western blot, dual-reporter assays and Chromatin immunoprecipitation (ChIP)-sequencing were used to analyze their relationship in vitro. Their roles in radioresistance were then investigated through multiple validation steps. NRF2 nuclear expression and SLC7A11 expression were overexpressed in ESCC tissues and were positively correlated with one another. NRF2 nuclear expression was significantly associated with tumor length, lymph node metastasis, and TNM stage, while SLC7A11 expression was associated with lymph node metastasis. Patients with high NRF2 nuclear expression and SLC7A11 expression had significantly shorter overall and progression-free survival, and poor treatment response. The multivariate model showed that NRF2 nuclear expression and SLC7A11 expression, sex and tumor location are independent prognostic factors. In vitro analysis confirmed that hyperactivation of NRF2 induced SLC7A11 expression by directly binding to its promoter region, promoting radioresistance, reducing radiotherapy-induced lipid peroxidation levels, PTGS2 expression, and radiotherapy-related ferroptosis morphologic features. Our study reveals a connection between high SLC7A11 expression and NRF2 nuclear expression in patients with ESCC that was related to worse survival and poorer therapy outcomes. SLC7A11-mediated ferroptosis inhibition induced NRF2-associated radioresistance, highlighting potential of NRF2/SLC7A11/ferroptosis axis as future therapeutic targets against therapy resistance biomarker.

中文翻译：

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NRF2调控的SLC7A11通过抑制铁死亡调节食管鳞状细胞癌放射敏感性

溶质载体家族7成员11（SLC7A11）是半胱氨酸/谷氨酸转运蛋白的组成部分，在肿瘤生长中起关键作用；然而，其对食管鳞状细胞癌 (ESCC) 放射敏感性的潜在影响仍不清楚。本研究旨在阐明 SLC7A11 在 ESCC 中的表达及其与核因子 erythroid-2 (NRF2) 相关放射抗性的核表达的相关性。我们纳入了 127 名接受根治性放化疗的 ESCC 患者。免疫组化染色检测SLC7A11和NRF2核表达，评价临床病理特征与生存率或治疗反应的关系。使用蛋白质印迹、双报告基因测定和染色质免疫沉淀 (ChIP) 测序在体外分析它们的关系。然后通过多个验证步骤研究它们在抗辐射性中的作用。NRF2 核表达和 SLC7A11 表达在 ESCC 组织中过度表达，并且彼此呈正相关。NRF2核表达与肿瘤长度、淋巴结转移和TNM分期显着相关，而SLC7A11表达与淋巴结转移相关。具有高 NRF2 核表达和 SLC7A11 表达的患者总体和无进展生存期显着缩短，治疗反应差。多变量模型显示NRF2核表达和SLC7A11表达、性别和肿瘤位置是独立的预后因素。体外分析证实 NRF2 的过度激活通过直接结合其启动子区域诱导 SLC7A11 表达，促进放射抗性，降低放疗诱导的脂质过氧化水平、PTGS2 表达和放疗相关的铁死亡形态学特征。我们的研究揭示了 ESCC 患者中高 SLC7A11 表达和 NRF2 核表达之间的联系，这与较差的生存率和较差的治疗结果有关。SLC7A11 介导的铁死亡抑制诱导 NRF2 相关的放射抗性，突出了 NRF2/SLC7A11/铁死亡轴作为未来治疗抗性生物标志物的治疗靶点的潜力。