From locus to gene: causal inference and experimental validation prioritize PSMA4 as a candidate target in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide, and although targeted therapy and immunotherapy have improved clinical outcomes, their long-term efficacy is frequently limited by therapeutic resistance, underscoring the need to identify additional biologically relevant and potentially actionable targets. In this study, we applied summary-data-based Mendelian randomization (SMR) by integrating lung cancer genome-wide association study (GWAS) summary statistics with cis-expression quantitative trait locus (cis-eQTL) and cis-methylation quantitative trait locus (cis-mQTL) datasets to prioritize candidate genes associated with LUAD risk. The robustness of SMR-significant signals was further evaluated using the heterogeneity in dependent instruments (HEIDI) test and Bayesian colocalization analysis. Independent transcriptomic datasets from the Gene Expression Omnibus (GEO), together with multiple public databases, were used for expression and prognostic validation, while protein-protein interaction (PPI) and functional enrichment analyses were performed to provide mechanistic context. Among 13 genes prioritized by integrative genetic analyses, PSMA4 (Proteasome 20S Subunit Alpha 4) emerged as the leading LUAD-relevant candidate on the basis of convergent multi-omics evidence, colocalization support, reproducible overexpression (OE) across independent cohorts, and adverse prognostic association. Functional experiments demonstrated that PSMA4 knockdown (KD) suppressed LUAD cell proliferation, migration, invasion, and xenograft tumor growth, whereas PSMA4 overexpression produced the opposite effects. Mechanistically, PSMA4 interacted with p53 and facilitated the proteasome-dependent turnover of ubiquitinated p53, as supported by co-immunoprecipitation, immunofluorescence, ubiquitination, proteasome inhibition, and cycloheximide chase assays, thereby attenuating p53 signaling. Collectively, these findings support PSMA4 as a biologically relevant and potentially actionable target in LUAD and provide a mechanistic rationale for further translational investigation.