Due to heterogenetic-specific nature of the available biomarkers, the incidence of lung adenocarcinoma (LUAD) is on the rise worldwide. Previously reported LUAD-related hub genes were searched from the medical literature via literature mining and were processed to identify few top genes via degree method. Later, a comprehensive in silico methodology was applied on the selected real hub genes to identify their tumor driving, diagnostic, and prognostic roles in LUAD patients with divers clinicopathological variables. Out of total 145 extracted hub genes, six genes including CDC6, PBK, AURKA, KIF2C, OIP5, and PRC1 were identified as real hub genes. The expression analysis showed that all these genes were significantly up-regulated across LUAD samples of different clinicopathological variables. In addition, a variety of unique correlations among the expression and of real hub genes and some other parameters including promoter methylation status, overall survival (OS), genetic changes, tumor purity, and immune cell infiltration have also been explored in the present study. Moreover, via TFS-miRNA-mRNA regulatory network, one important TF (E2F1) and one important miRNAs (hsa-mir-34a-5p) that targeted all the real hub genes were also identified. Finally, a variety of drugs also predicted to be very useful in treating LUAD. The discovery of the real hub genes, TFS-miRNA-mRNA network, and chemotherapeutic drugs associated with LUAD provides new insights into underlying mechanisms and treatment of LUAD overcoming heterogeneity barriers.