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Abstract Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortalities, characterized by substantial genetic heterogeneity that challenges a comprehensive understanding of its progression. This study employs next-generation sequencing data analysis to transform our comprehension of LUAD pathogenesis. Integrating epigenetic and transcriptomic data of LUAD patients, this approach assessed the critical regulatory occurrences, identified therapeutic targets, and offered profound insights into cancer molecular foundations. We employed the DNA methylation data to identify differentially methylated CpG sites and explored the transcriptome profiles of their adjacent genes. An intersectional analysis of gene expression profiles uncovered 419 differentially expressed genes (DEGs) influenced by smoke-induced differential DNA methylation, among which hub genes, including mitochondrial ribosomal proteins (MRPs), and ribosomal proteins (RPs) such asMRPS15,MRPS5,MRPL33,RPL24,RPL7L1,MRPL15,TUFM,MRPL22, andRSL1D1, were identified using a network-based approach. These hub genes were overexpressed and enriched to RNA processing, ribosome biogenesis, and mitochondrial translation, which is critical in LUAD progression. Enhancer Linking Methylation/Expression Relationship (ELMER) analysis revealed transcription factor (TF) binding motifs, such asJUN,NKX23,FOSB,RUNX3, andFOSL1, which regulated these hub genes through methylation-dependent enhancer dynamics. Predominant hypomethylation of MRPs and RPs disrupted mitochondrial function, contributed to oxidative phosphorylation (OXPHOS) and metabolic reprogramming, favoring cancer cell survival. The survival analysis validated the clinical relevance of these hub genes, with high-expression cohorts exhibiting poor overall survival (OS) outcomes enlightened their relevance in LUAD pathogenesis and presented the potential for developing novel targeted therapeutic strategies.