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

## TL;DR

This study explores how targeting the NPY5R receptor with Euphorbia Factor L2 could help treat lung adenocarcinoma by inhibiting cancer cell growth and migration.

## Contribution

The study identifies NPY5R as a novel therapeutic target and demonstrates the antitumor potential of EFL2 through pharmacological and transcriptomic analyses.

## Key findings

- High NPY5R expression correlates with poor prognosis and immune cell infiltration in lung adenocarcinoma.
- EFL2 inhibits cancer cell proliferation and migration while inducing apoptosis via NPY5R targeting.
- NPY5R knockdown combined with EFL2 treatment synergistically activates key cancer-related signaling pathways.

## Abstract

Background: 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). Methods: Bioinformatics analyses were performed to evaluate NPY receptors in LUAD. Lentivirus-mediated stable neuropeptide Y receptor 5 (NPY5R) 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 NPY5R. Results: High expression of NPY5R correlated with poor prognosis and immune cell infiltration in LUAD. EFL2 targeted NPY5R, inhibiting A549 cell proliferation and migration while inducing apoptosis. NPY5R knockdown further enhanced these antitumor effects, and the combination of NPY5R 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. Conclusions: NPY5R is a promising therapeutic target for LUAD. While no clinical drugs targeting NPY5R are currently available, preclinical evidence supports its potential for anticancer drug development. EFL2 exerts antitumor effects via targeting NPY5R, offering useful guidance for developing novel LUAD therapies.