Integrating Human Proteomes with Genome-Wide Association Data Reveals Prioritized Therapeutic Candidates for Lung Squamous Cell Carcinoma

Lung squamous cell carcinoma (LUSC) is the second most prevalent type of lung cancer worldwide. Despite its global health burden, the molecular mechanisms driving LUSC remain poorly characterized, posing considerable challenges for the development of targeted preventive therapies. Here, by integrating human plasma proteomes (<i>n</i> = 54,219) with GWAS summary data for LUSC (7426 cases and 55,627 controls), we performed genome-wide Mendelian randomization (MR) and colocalization analyses to identify potential druggable targets associated with LUSC risk. After applying Bonferroni correction, sensitivity analyses, and reverse causation detection, we identified 12 potential druggable proteins significantly associated with LUSC risk. Five of these proteins (DOK2, FKBPL, NCF2, PDIA3, and TCL1A) showed strong evidence of colocalization. Furthermore, protein-protein interaction (PPI) networks and druggability assessments were used to refine therapeutic target selection. Additionally, mediation analyses were performed to elucidate the mediating effects of modifiable risk factors on the relationship between plasma proteins and LUSC risk, and we identified 14 modifiable risk factors that could mitigate LUSC risk through targeted interventions. More importantly, we stratified the 12 proteins into four tiers based on colocalization, differential expression, PPI networks, and druggability potential. Notably, DOK2 emerged as a Tier 1 target, while FKBPL, NCF2, AXL, and PDIA3 were classified as Tier 2 targets, representing promising candidates for further drug development. Overall, we identified 12 proteins with druggable potential associated with LUSC risk and demonstrated how modifiable risk factors mediate these associations. These findings advance our understanding of LUSC etiology and provide a foundation for developing targeted therapeutic strategies while emphasizing the importance of addressing modifiable risk factors in both prevention and treatment efforts.