Radioresistance becomes the major obstacle to reduce tumor recurrence and improve prognosis in the treatment of esophageal squamous cell carcinoma (ESCC). Thus new strategies for radioresistant ESCC are urgently needed. Herein, we reported that tribbles pseudokinase 3 (TRIB3) serves as a key regulator of radioresistance in ESCC. TRIB3 is overexpressed in ESCC tissues and cell lines. High expression of TRIB3 significantly correlates with poor radiotherapy response and prognosis in ESCC patients. Upregulation of TRIB3 in ESCC cells conferred radioresistance in vitro and in vivo by interacting with TAZ thus impeding β-TrCP-mediated TAZ ubiquitination and degradation. Conversely, silencing TRIB3 sensitized ESCC cells to ionizing radiation. More importantly, TRIB3 was significantly correlated with TAZ activation in ESCC biopsies, and patients with high expression of both TRIB3 and TAZ suffered the worst radiotherapy response and survival. Our study uncovers the critical mechanism of ESCC resistance to radiotherapy, and provides a new pharmacological opportunity for developing a mechanism-based strategy to eliminate radioresistant ESCC in clinical practice.

放射抗性成为食管鳞状细胞癌（ESCC）治疗中减少肿瘤复发、改善预后的主要障碍。因此，迫切需要针对抗辐射 ESCC 的新策略。在此，我们报道了 tribbles 假激酶 3 (TRIB3) 是 ESCC 放射抗性的关键调节因子。TRIB3 在 ESCC 组织和细胞系中过度表达。TRIB3的高表达与食管鳞癌患者的放疗反应不良和预后显着相关。ESCC 细胞中 TRIB3 的上调通过与 TAZ 相互作用在体外和体内赋予放射抗性，从而阻止 β-TrCP 介导的 TAZ 泛素化和降解。相反，沉默 TRIB3 会使 ESCC 细胞对电离辐射敏感。更重要的是，TRIB3 与 ESCC 活检中的 TAZ 激活显着相关，TRIB3和TAZ同时高表达的患者的放疗反应和生存率最差。我们的研究揭示了食管鳞癌对放疗耐药的关键机制，并为在临床实践中开发基于机制的策略来消除放疗耐药食管癌提供了新的药理学机会。