Radioresistance remains the most challenging issue leading to radiotherapy failure in the treatment of non-small cell lung cancer (NSCLC). The nuclear factor IA (NFIA) is associated with tumor response to treatments in many cancers, but its role in NSCLC radioresistance remains unclear. Here, we established two radioresistant NSCLC cell lines, H226R and H460R, by dose-gradient irradiation to investigate the function of NFIA in NSCLC radioresistance. The results showed a dramatically reduced expression of NFIA in radioresistant cells accompanied with elevated phosphorylation of AKT and ERK, when compared with their parental cells. Overexpression of NFIA restored the sensitivity of radioresistant cells to radiation through increased ionizing radiation (IR)-induced apoptosis and DNA damage by downregulating p-ART and p-ERK, whereas knockdown of NFIA promoted radioresistance of the parental cells. Our findings suggested that NFIA enhanced cell radiosensitivity by downregulating p-ART and p-ERR in NSCLC. Our study fills a gap in the field of NFIA and radioresistance, and establishes a mechanistic foundation to improve radiotherapy efficiency in NSCLC patients. (C) 2019 Elsevier Inc. All rights reserved.