Identification of C4BPA as a genetically informed drug target in NSCLC: An integrative single-cell and multi-omics study based on the druggable genes

Background Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Despite advancements in treatment, drug resistance and limited therapeutic efficacy persist, underscoring the urgent need for novel and mechanistically informed therapeutic strategies. Identifying genetically supported drug targets may accelerate the development of precision therapies in NSCLC. Methods We implemented an integrative multi-omics framework combining single-cell RNA sequencing (scRNA-seq), genome-wide association studies (GWAS), and molecular quantitative trait locus (QTL) datasets including expression (eQTL), protein (pQTL), and DNA methylation (mQTL) QTLs. Druggable candidates were systematically evaluated using a suite of Mendelian randomization (MR) approaches—including summary data-based MR (SMR), generalized SMR (GSMR), and genetic risk score (GRS) analysis. Epigenetic regulation and downstream signaling were further explored through mediation MR analysis. Results C4BPA, a complement-regulatory macromolecule, emerged as a causal risk factor for NSCLC across multiple MR models, with consistent findings validated at both transcriptomic and proteomic levels. Epigenetic activation of C4BPA via DNA methylation was observed, and C4BPA expression was shown to promote NSCLC progression through the inflammatory chemokine CCL8 signaling axis. Sensitivity analyses confirmed the robustness of causal inference with no evidence of horizontal pleiotropy. Conclusions Our findings identify C4BPA as a genetically validated and biologically plausible therapeutic target for NSCLC. This study demonstrates the power of integrating single-cell transcriptomics with population-scale omics and causal inference to uncover actionable targets, offering a scalable framework for advancing precision oncology in lung cancer.