Esophageal squamous cell carcinoma (ESCC) is a common malignant cancer worldwide. Despite recent improvements in surgical techniques and adjuvant therapies, the prognosis of patients with advanced ESCC remains poor. Resistance to chemoradiotherapy (CRT) remains a major cause of treatment failure for advanced ESCC patients. Here, we report that NRIP3 (nuclear receptor interacting protein 3) promotes ESCC tumor cell growth and resistance to CRT in ESCC cells by increasing and binding to DDI1 (DNA-damage inducible 1 homolog 1) and RTF2 (homologous to Schizosaccharomyces pombe Rtf2), and accelerating the removal of RTF2, which is a key determinant for the ability of cells to manage replication stress. In addition, we found that NRIP3 could increase DDI1 expression via PPARα. The NRIP3-PPARα-DDI1-RTF2 axis represents a protective molecular pathway in ESCC cells that mediates resistance to replication stress signals induced by chemoradiotherapy. In addition, elevated NRIP3 is associated with the poor clinical outcome of ESCC patients receiving radiotherapy and/or cisplatin-based chemotherapy. Our study therefore reveals that NRIP3 is a prognostic factor in ESCC and could have some predictive value to select patients who benefit from CRT treatment. A common mechanism that protects ESCC tumor cells from DNA damage induced by CRT is also revealed in this study.

食管鳞状细胞癌（ESCC）是世界范围内常见的恶性肿瘤。尽管最近手术技术和辅助治疗有所改进，但晚期食管鳞癌患者的预后仍然很差。放化疗（CRT）耐药仍然是晚期食管鳞癌患者治疗失败的主要原因。在这里，我们报道NRIP3（核受体相互作用蛋白3）通过增加和结合DDI1（DNA损伤诱导1同源物1）和RTF2（与粟酒 裂殖酵母Rtf2同源）来促进ESCC肿瘤细胞生长和ESCC细胞对CRT的抵抗，并加速 RTF2 的去除，RTF2 是细胞管理复制压力能力的关键决定因素。此外，我们发现NRIP3可以通过PPARα增加DDI1的表达。NRIP3-PPARα-DDI1-RTF2 轴代表 ESCC 细胞中的保护性分子途径，介导对放化疗诱导的复制应激信号的抵抗。此外，NRIP3升高与接受放疗和/或顺铂化疗的食管鳞癌患者的不良临床结果相关。因此，我们的研究表明，NRIP3 是 ESCC 的一个预后因素，对于选择从 CRT 治疗中受益的患者可能具有一定的预测价值。这项研究还揭示了保护 ESCC 肿瘤细胞免受 CRT 诱导的 DNA 损伤的常见机制。