Multi-omics and experimental validation unveil BDNF as a diagnostic biomarker and therapeutic target in endoplasmic reticulum stress-driven lung adenocarcinoma: Therapeutic potential of Esketamine.

Endoplasmic reticulum stress (ERS) has shown notable antitumor potential by regulating malignant tumor progression, metastasis and immune response activation. The aim of the present study was to further explore the potential function of brain-derived neurotrophic factor (BDNF), a representative of ERS-related gene (ERSG), in lung adenocarcinoma (LUAD) and to verify the application potential of BDNF-related Esketamine for LUAD. A multi-omics integrated analysis was used to analyze the relevant ERS and LUAD data obtained from public databases, systematically screening and identifying expressed ERSGs in LUAD. The role of ERSGs within the tumor microenvironment was assessed through single-cell transcriptome data analysis, and distinct immune landscapes in LUAD were delineated based on bulk RNA-seq data. Machine learning was used to construct a robust ERS-related predictive model for accurately forecasting the prognosis of patients with LUAD. The causal relationship between the representative ERSG BDNF and LUAD was evaluated using summary-data-based Mendelian randomization (SMR) and colocalization analyses. The elevated expression of BDNF in A549 and BEAS-2B cells was validated using reverse transcription-quantitative (RT-q) PCR. Loss-of-function experiments using small interfering RNA (siRNA) were used to knock down BDNF expression in A549 cells (A549BDNF-siRNA) and the proliferation capacity of A549BDNF-siRNA was verified using Cell Counting Kit-8 (CCK-8) and colony formation assays. Approved drugs targeting BDNF were screened, followed by molecular docking to evaluate the binding affinity of BDNF to these drugs. The inhibitory effect of Esketamine on A549 cell proliferation was examined using CCK-8 and colony formation assays. The efficacy of Esketamine at inhibiting A549 cell invasion and migration was assessed using Transwell and wound healing assays. TUNEL assay and western blotting were used to analyze the apoptosis of A549 cells induced by Esketamine. A total of 67 ERSGs were screened and identified. Integrating prognostic analysis, single-cell transcriptomic data and RNA-seq, BDNF emerged as a gene of significant research potential. SMR and colocalization analyses indicated a potential causal relationship between BDNF and LUAD. RT-qPCR revealed that BDNF was expressed at high levels in A549 cells, and BDNF knockdown markedly inhibited their proliferation. Esketamine, which can inhibit BDNF, was found to effectively suppress the proliferation, invasion and migration of A549 cells, while inducing apoptosis. BDNF is expressed at high levels in A549 cells, and the inhibition of its expression by Esketamine may have good potential in inhibiting LUAD.