ADAR1 regulates radiosensitivity in ESCC through cIAP2-NF-κB signaling and C16orf46 editing

Esophageal squamous cell carcinoma (ESCC) frequently exhibits resistance to radiotherapy, limiting treatment efficacy. We investigated the role of an RNA-editing enzyme, adenosine deaminase acting on RNA (ADAR1), in regulating radiosensitivity, using patient samples, ESCC cell lines, and xenograft models. ADAR1 showed high expression in ESCC and was associated with a poor response to neoadjuvant chemoradiotherapy. ADAR1 loss suppressed tumor growth and enhanced radiosensitivity in vitro and in vivo. ADAR1 depletion promoted gasdermin E (GSDME)-mediated pyroptosis, thereby sensitizing tumor cells to irradiation. Transcriptome-wide RNA-editing analysis identified C16orf46 (chromosome 16 open reading frame 46) as a functionally relevant ADAR1-dependent editing target, and reduced editing of C16orf46 contributed to radiosensitization. ADAR1 depletion also altered cIAP2 (cellular inhibitor of apoptosis protein 2) and NF-κB signaling, suggesting an additional RNA editing-independent mechanism. These findings identify ADAR1-dependent RNA editing as a regulator of ESCC radiotherapy response and support ADAR1 as a potential target for radiosensitization.