Radioresistance is one of the main causes for local treatment failure in lung cancer. Nevertheless, the potential mechanisms of radioresistance in lung cancer have not been elucidated completely. Here, we discover a carcinoma-inhibiting protein called leucine zipper tumor suppressor 3 (LZTS3), which is low-expressed and related to adverse outcome in lung cancer. Moreover, our studies demonstrate that LZTS3 restrains cell proliferation and radioresistance in vitro and in vivo. Mechanistically, protein kinase CK1δ interacts with LZTS3, resulting in E3 ubiquitin ligase β-TrCP recognizes and binds to LZTS3. Thus, LZTS3 is degraded by the ubiquitin-proteasome pathway. We also identify two conserved degrons (DSGRNS and DSGRAS) are essential for the ubiquitinated degradation of LZTS3 by CK1δ and β-TrCP. More importantly, we detect that the CK1δ and β-TrCP-mediated degradation of LZTS3 facilitate the cell growth, proliferation and radioresistance in lung cancer. Collectivelly, our results suggest that LZTS3 regulates tumorigenesis and radioresistance in lung cancer depend on a CK1δ and β-TrCP-mediated ubiquitin-proteasome pathway. LZTS3 may be a new molecular target for lung cancer treatment.