Current targeted therapies for non-small cell lung cancer (NSCLC) face significant limitations, primarily due to the small proportion of patients who respond to existing targets and the development of drug resistance. Consequently, identifying novel therapeutic targets is crucial to overcome these challenges. In this study, we identified Neurolysin (NLN) as a novel therapeutic target for NSCLC using high-throughput proteomics. We validated the oncogenic role of NLN through in vitro cellular models and in vivo studies, and uncovered a previously unrecognized mechanism in ferroptosis regulation. We demonstrated that NLN expression was significantly upregulated in lung cancer tissues relative to adjacent normal tissues. More notably, inhibition of NLN induced ferroptosis in lung cancer cells. In vivo studies confirmed that the suppression of NLN significantly inhibited tumor growth in a mouse model. Mechanistic investigations revealed that NLN inhibition reduced the m6A modification of GPX4 mRNA, resulting in its degradation and the subsequent induction of ferroptosis. Moreover, we developed a specific small molecule inhibitor, NR2, which targets NLN and induces tumor cell death both in vitro and in vivo, showcasing potent anti-tumor activity. These findings not only establish NLN as a crucial regulator of ferroptosis in NSCLC but also provide a novel therapeutic strategy to target ferroptosis in lung cancer. Our work offers a scientific foundation for the clinical development of NLN-targeted therapies in NSCLC, addressing both the challenges of drug resistance and tumor progression.Copyright © 2025. Published by Elsevier B.V.