Targeting NPY5R—A Member of the NPY Receptor Family: Pharmacological and Transcriptomic Mechanisms of the Euphorbia Factor L2 Against Lung Adenocarcinoma

<b>Background</b>: Advanced lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths, with existing treatments hampered by drug resistance. This underscores the urgent need to identify novel therapeutic targets. The role of neuropeptide Y (NPY) receptors in LUAD remains unclear, and this study aimed to investigate their expression profiles, prognostic significance, and the antitumor potential of Euphorbia Factor L2 (EFL2). <b>Methods</b>: Bioinformatics analyses were performed to evaluate NPY receptors in LUAD. Lentivirus-mediated stable neuropeptide Y receptor 5 (<i>NPY5R</i>) knockdown, functional assays including CCK-8, flow cytometry, and scratch assay, PRESTO-Tango, RNA sequencing (RNA-seq), and qPCR were employed to validate the antitumor effects of EFL2 and the functional role of <i>NPY5R</i>. <b>Results</b>: High expression of <i>NPY5R</i> correlated with poor prognosis and immune cell infiltration in LUAD. EFL2 targeted <i>NPY5R</i>, inhibiting A549 cell proliferation and migration while inducing apoptosis. <i>NPY5R</i> knockdown further enhanced these antitumor effects, and the combination of <i>NPY5R</i> knockdown and EFL2 treatment synergistically enriched extracellular matrix (ECM), phosphatidylinositol 3-kinase (PI3K)-Akt, and mitogen-activated protein kinase (MAPK) pathways. Four potential molecular targets were identified. <b>Conclusions</b>: <i>NPY5R</i> is a promising therapeutic target for LUAD. While no clinical drugs targeting <i>NPY5R</i> are currently available, preclinical evidence supports its potential for anticancer drug development. EFL2 exerts antitumor effects via targeting <i>NPY5R</i>, offering useful guidance for developing novel LUAD therapies.