Neuroepithelial cell transforming 1 as a key regulator in non-small cell lung cancer: unveiling causal links and...

High incidence and mortality rates underscore lung cancer as a significant global health issue. Understanding the molecular mechanisms driving its progression is crucial for developing effective treatments. This study explores a potential molecular regulator that may contribute to the progression of non-small cell lung cancer (NSCLC) by utilizing bioinformatics analyses and laboratory experiments, aiming to provide insights that could inform future therapeutic strategies.

Our research combined single-cell RNA sequencing (scRNA-seq) data analysis with the Mendelian randomization (MR) algorithm. MR analysis using genetic variants associated with NSCLC risk aimed to uncover causal relationships between genes and cancer traits. To validate the impact of neuroepithelial cell transforming 1 (NET1) on cellular proliferation and its role in inhibiting ferroptosis, we utilized quantitative real-time polymerase chain reaction (qRT-PCR), cell viability assays, and malondialdehyde (MDA) detection. Furthermore, molecular docking analyses of four compounds demonstrated their potential in modulating the downregulation of NET1.

ScRNA-seq exposed cellular diversity in non-malignant lungs and tumors. Distinct expression patterns in epithelial cells and identified gene pathways pointed to cell proliferation. NET1, causally linked to NSCLC through MR analysis, showed increased expression in tumors and correlated with unfavorable overall survival, validated by functional assays. Utilizing cell viability assays and MDA detection, our results validated the pivotal role of NET1 in enhancing cellular proliferation and its efficacy in inhibiting ferroptosis. Doxorubicin, piroxicam, and quercetin emerged as potential drug candidates for NSCLC treatment based on molecular docking analysis.

Our findings confirm NET1's significant role in NSCLC progression, influencing cell proliferation, ferroptosis, immune activity regulation and identify potential therapeutics for targeted lung cancer treatment.