Background: Lung adenocarcinoma (LUAD) is characterized by a high propensity for metastasis and poor patient outcomes, along with reduced survival rates. This study aims to investigate the role of pleckstrin-homology-like domain family-A member 2 (PHLDA2) in the progression of LUAD and its transcriptional regulation by the ETS-like-1 protein (ELK1).

Methods: PHLDA2 expression was analyzed in The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA-LUAD) (gene expression profiling interactive analysis (GEPIA)) and validated in LUAD cell lines using Western blot (WB) analysis. Functional analyses, including the counting kit-8 (CCK-8) proliferation curves, Transwell migration/invasion, apoptosis, and cisplatin half-maximal inhibitory concentration (IC₅₀) determination, were performed after silencing PHLDA2 (siPHLDA2). Additionally, chromatin immunoprecipitation (ChIP)-quantitative polymerase chain reaction (qPCR) and dual-luciferase reporter assays were used to evaluate ELK1's binding and promoter activation.

Results: PHLDA2 was significantly upregulated in LUAD tumors compared to normal lung tissues (p < 0.05), and high PHLDA2 expression was associated with shorter overall survival (Kaplan–Meier, p = 0.02). Silencing PHLDA2 reduced proliferation, reversed epithelial-mesenchymal transition (EMT), diminished migration/invasion, and increased cisplatin sensitivity (IC₅₀ ≈ 16 μM vs. ≈ 36 μM in controls). ELK1 bound a –420 bp motif in the PHLDA2 promoter and enhanced its transcription (≈3-fold).

Conclusion: These results suggest that the ELK1-PHLDA2 axis promotes LUAD malignancy and chemoresistance and may represent a potential therapeutic target, warranting in vivo and clinical validation.