Lung adenocarcinoma (LUAD) remains the leading cause of cancer-related mortality worldwide. Unlike patients harboring epidermal growth factor receptor (EGFR) mutations, those with wild-type EGFR lack effective targeted therapeutic options. We established a super-SILAC-based proteomic dataset (PXD046807) comprising LUAD tissues stratified by EGFR mutation status and clinical stages. Notably, myeloid-derived growth factor (MYDGF) was identified as a potential key regulator in patients with wild-type EGFR LUAD. To further investigate the role of MYDGF in LUAD, we applied gene knockdown combined with tandem mass tag (TMT)-based quantitative proteomic analysis to search for the specific biological processes regulated by MYDGF in normal lung fibroblasts and LUAD cells with different EGFR status.