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Radiotherapy has shown measurable efficacy in breast cancer (BC). Elucidating the mechanisms and developing effective strategies against resistance, which is a major challenge, is crucial. Mitochondria, which regulate homeostasis of the redox environment, have emerged as a radiotherapeutic target. However, the mechanism via which mitochondria are controlled under radiation remains elusive. Here, we identified alpha-enolase (ENO1), as a prognostic marker for the efficacy of BC radiotherapy. ENO1 enhances radio-therapeutic resistance in BC via reducing the production of reactive oxygen species (ROS) and apoptosis in vitro and in vivo through modulation of mitochondrial homeostasis. Moreover, LINC00663 was identified as an upstream regulator of ENO1, which regulates radiotherapeutic sensitivity by downregulating ENO1 expression in BC cells. LINC00663 regulates ENO1 protein stability by enhancing the E6AP-mediated ubiquitin-proteasome pathway. In BC patients, LINC00663 expression is negatively correlated with ENO1 expression. Among patients treated with IR, those who did not respond to radiotherapy expressed lower levels of LINC00663 than those sensitive to radiotherapy. Our work established LINC00663/ENO1 critical to regulate IR-resistance in BC. Inhibition of ENO1 with a specific inhibitor or supplement of LINC00663 could be potential sensitizing therapeutic strategies for BC. • ENO1 is a prognostic marker for radiotherapy efficacy in breast cancer (BC). • ENO1 enhances IR-resistance in BC by reducing apoptosis and ROS production. • LINC00663 is a novel upstream regulator of ENO1 expression. • It regulates radiotherapeutic sensitivity by downregulating expression in BC cells. • LINC00663 regulates the ENO1 protein. [ABSTRACT FROM AUTHOR]