AbstractBackgroundsCircRNA hsa_circ_0004396 has been confirmed to be upregulated in human non‐small cell lung cancer (NSCLC). The aim of his study was to evaluate its mechanism in the radioresistance and progression of NSCLC.MethodsHsa_circ_0004396, miR‐615‐5p, and P21‐Activated Kinase 1 (PAK1) were measured by reverse transcription quantitative real‐time polymerase chain reaction (RT‐qPCR). The binding between miR‐615‐5p and hsa_circ_0004396 or PAK1 was predicted by circinteractome or Targetscan, as verified by dual‐luciferase reporter assay and RIP assay. Proliferation, clonogenicity capacity, cell cycle progression, apoptosis, migration, and invasion were assessed by CCK‐8, colony formation, flow cytometry, and Transwell assay. Bcl‐2, Bcl‐2 associated protein X (Bax), MMP‐2, and PAK1 protein levels were detected using western blot assay. In addition, in vivo function of hsa_circ_0004396 was evaluated by tumor xenograft assay.ResultsHsa_circ_0004396 and PAK1 levels were upregulated, while miR‐615‐5p was declined in NSCLC. Hsa_circ_0004396 silencing inhibited NSCLC cell malignant behavior and induced radiosensitivity. Hsa_circ_0004396 functions as a molecular sponge of miR‐615‐5p to regulate PAK1 expression. Moreover, hsa_circ_0004396 knockdown inhibited NSCLC tumor growth in vivo.ConclusionOur findings demonstrated that hsa_circ_0004396 promoted NSCLC development and radioresistance through the miR‐615‐5p/PAK1 axis, which might provide a new therapeutic target for NSCLC treatment.