Integrative Multi-omics Analysis and Mendelian Randomization Reveal Potential Therapeutic Targets and their Stratification in Lung Squamous Cell Carcinoma.

[BACKGROUND] Lung Squamous Cell Carcinoma (LUSC), a major subtype of non-small cell lung cancer, presents significant treatment challenges due to limited targeted therapy options. This study aims to identify novel therapeutic targets to improve therapeutic strategies for LUSC.

[METHODS] By employing bulk RNA sequencing, Weighted Gene Co-expression Network Analysis (WGCNA), survival analysis, and Mendelian Randomization (MR), we pinpointed genes with prognostic relevance to LUSC. These genes were further scrutinized for their therapeutic potential through LASSO regression, Protein-Protein Interaction (PPI) network analysis, and immune infiltration assessments. To delve into the roles and cell-specific expressions of these genes within the LUSC microenvironment, pathway enrichment analysis, single-cell RNA sequencing (scRNA-seq), and pseudotime analysis were conducted.

[RESULTS] Our integrative approach identified 23 prognostically significant therapeutic targets, categorized into tier-one, tier-two, and tier-three genes based on their potential therapeutic relevance. Functional enrichment analyses highlighted the significant role of these genes in immune response regulation, particularly in T-cell receptor signaling and the complement system. scRNA-seq analysis revealed cell-type-specific expression patterns and pseudotime analysis provided insights into cellular heterogeneity and developmental trajectories in LUSC.

[CONCLUSION] In this study, we identified 3 tier-one genes (MCM6, C4B, CTC-463A16.1), 7 tier-two genes (C4A, HLA-DRB9, LIMS2, LINC00654, MYO7B, SIGLEC5, TIE1), and 13 tier-three genes (AC007743.1, AC147651.4, ALDH2, BTN3A2, BTNL9, CCR1, GIPC3, HLA-DQB1, ICAM5, LIMD1, PM20D1, RP11-302L19.3, RP11-768F21.1).