Multi-omics profiling reveals PLEKHA6 as a modulator of β-catenin signaling and therapeutic vulnerability in lung adenocarcinoma

Lung adenocarcinoma (LUAD) remains the most prevalent and lethal subtype of lung cancer, largely due to late diagnosis and therapeutic resistance. In this study, we conducted a comprehensive multi-omics analysis to characterize the pleckstrin homology domain-containing (PLEKHA) family gene in LUAD. Among the eight members, PLEKHA6 was uniquely overexpressed in LUAD tissues and significantly associated with poor prognosis. Integrated bulk RNA-Seq, single-cell RNA-Seq, DNA methylation, and pharmacogenomic analyses identified PLEKHA6 as a key modulator of oncogenic processes, including Wnt/β-catenin signaling, cadherin-mediated adhesion, and cytoskeletal remodeling. Functional assays in A549 LUAD cells revealed that PLEKHA6 knockdown suppressed β-catenin and VE-cadherin expression, leading to impaired proliferation, migration, and colony formation, along with enhanced apoptosis and cell cycle arrest. Single-cell RNA sequencing demonstrated a correlation between PLEKHA6 expression and tumor-associated macrophage (TAM) infiltration, implicating PLEKHA6 in immune remodeling within the tumor microenvironment (TME). Drug sensitivity analysis and molecular docking further identified potential therapeutic drugs targeting PLEKHA6-expressing LUAD cells. Collectively, our findings establish PLEKHA6 as a novel oncogenic driver and immune modulator in LUAD, supporting its potential as both a prognostic biomarker and a therapeutic target for precision oncology.