Background <p>Radiation resistance in lung adenocarcinoma (LUAD) remains a primary obstacle limiting radiotherapy efficacy. However, the detailed factors and molecular mechanisms influencing LUAD radiosensitivity are not fully understood.</p> Methods <p>Radioresistance-related genes (RRRGs) were screened by RNA sequencing and bioinformatics analysis, and a prediction model for radiotherapy efficacy was developed via LASSO-Cox regression analysis. We specifically focused on Stanniocalcin 2 (STC2) due to its prognostic significance and validated its expression through immunohistochemical staining (IHC) in pathological samples from LUAD patients. A STC2 knockdown (siSTC2) A549 cell line was created, and Western blotting, CCK8, and colony formation assays were performed to investigate STC2’s involvement in radioresistance.</p> Results <p>An efficacy prediction model was constructed using 6 RRRGs (FCGBP, SLCO4A1, ALDH3A1, STC2, TERT, CYP24A1). IHC analysis of 74 LUAD patients showed significantly higher STC2 expression in radiotherapy non-responders (N-Res) versus responders (Res) (<i>p</i> &lt; 0.05). Patients with elevated STC2 levels experienced shorter overall survival (OS). Western blotting revealed higher STC2 expression in irradiated (IR) A549 cells compared to non-irradiated (N-IR) (<i>p</i> &lt; 0.05). CCK8 assays results suggested that knockdown of STC2 resulted in a significant reduction in cell proliferation ability (<i>p</i> &lt; 0.05), and colony formation assays confirmed a significant decrease in clonogenic ability of siSTC2 cells compared to controls (<i>p</i> &lt; 0.05).</p> Conclusion <p>STC2 plays a significant role in mediating LUAD cell radioresistance, with high expression correlating with poor prognosis. Therefore, STC2 represents a promising therapeutic target for overcoming LUAD radioresistance.</p> Clinical trial number <p>Not applicable.</p>