Dual mechanisms of ADAR1 in regulating radiosensitivity in ESCC via pyroptosis through the cIAP2/NF-κB pathway and C16orf46 RNA editing

Many patients with esophageal squamous cell carcinoma (ESCC) exhibit poor responses to radiotherapy, often due to radioresistance that impairs treatment efficacy. Aberrant adenosine-to-inosine (A-to-I) RNA editing, mediated by ADAR1, plays a crucial regulatory role in the occurrence and development of cancer. To investigate whether ADAR1 contributes to radioresistance in ESCC, we conducted a multi-tiered analysis incorporating clinical data, cellular experiments, and in vivo tumor models. We discovered that ADAR1 was significantly upregulated in ESCC tumor tissues compared to adjacent non-tumorous tissue, and its high expression was associated with a poorer clinical response to neoadjuvant chemoradiotherapy (nCRT). Targeted inactivation of ADAR1 inhibited ESCC cell proliferation and enhanced radiosensitivity both in vitro and in vivo. Mechanistically, ADAR1 depletion promoted GSDME-mediated pyroptosis, thereby sensitizing tumor cells to irradiation. Notably, this effect was mediated through two distinct mechanisms: an RNA editing-independent pathway involving cIAP2 upregulation and activation of nuclear factor-kappa B (NF-κB) signaling, and an RNA editing-dependent mechanism driven by reduced A-to-I editing of C16orf46. Our data supported A-to-I RNA editing as a functional contributor to radioresistance in ESCC, providing new insights and a rationale for targeting ADAR1 as a therapeutic strategy to overcome radioresistance.