Identification and Functional Validation of PTH2R as a Therapeutic Target in Lung Adenocarcinoma

Background: One of the main causes of cancer-related mortality globally is lung adenocarcinoma (LUAD), necessitating the development of novel therapeutic targets. The parathyroid hormone type 2 receptor (PTH2R) exhibits differential expression across multiple cancers, yet its role in LUAD remains unclear. Methods: Through an integrated analysis of multiple public databases (including SangerBox 3.0, UALCAN, Kaplan–Meier Plotter, and TIMER), we identified PTH2R—a member of the family B1 GPCRs—as a candidate therapeutic target with significant prognostic value in LUAD. Subsequently, the antitumor effects of PTH2R knockdown and melatonin were evaluated through cell proliferation, colony formation, migration, and apoptosis assays. Transcriptome analysis revealed key biological processes and signaling pathways regulated by PTH2R, identified key genes modulated by PTH2R, and validated core gene expression via RT-qPCR. Results: PTH2R is a potential therapeutic target for lung adenocarcinoma. Both PTH2R knockdown and melatonin treatment significantly inhibited LUAD cell proliferation, colony formation, and migration capabilities while promoting apoptosis. Notably, the combination of PTH2R knockdown and melatonin treatment demonstrated synergistically enhanced antitumor effects. Transcriptome analysis revealed two key genes within the PTH2R signaling pathway, and RT-qPCR validated the expression of these two key genes. Conclusions: Our work provides the first evidence confirming the substantial value of PTH2R as a novel therapeutic target for LUAD. It preliminarily demonstrates the mechanism by which melatonin inhibits LUAD by targeting PTH2R, offering crucial experimental evidence and theoretical support for developing precision therapeutic strategies against this cancer.