<i>ZNF528</i> as a novel driver of metastasis in lung cancer: insights from single-cell transcriptomics

<h4>Background</h4>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality due to frequent metastasis, despite therapeutic advances. This study aims to identify novel drivers of NSCLC metastasis to facilitate the development of prognostic biomarkers and therapeutic targets.<h4>Methods</h4>We analyzed single-cell RNA-seq data (GSE121907) to identify differentially expressed genes (DEGs) in epithelial cells from metastatic NSCLC. Functional enrichment was performed. Based on bioinformatic findings, we investigated the role of zinc finger protein 528 (<i>ZNF528</i>) through gain- and loss-of-function studies in NSCLC cell lines. Cellular proliferation, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8), wound healing, and Transwell assays, respectively. Epithelial-mesenchymal transition (EMT) markers were analyzed by immunoblotting. A cell-derived xenograft (CDX) model was established to evaluate tumor growth and metastasis <i>in vivo</i>.<h4>Results</h4>Single-cell analysis revealed an expanded epithelial compartment in metastatic samples. Among the DEGs identified in these epithelial cells, <i>ZNF528</i> was significantly upregulated. Pathway analysis indicated enrichment of <i>ZNF528</i>-correlated genes in proliferation and invasion-related pathways (e.g., NF-κB, MAPK). Consistently, functional assays demonstrated that <i>ZNF528</i> knockdown suppressed, while its overexpression enhanced, NSCLC cell proliferation, migration, invasion, and EMT <i>in vitro</i>. Moreover, <i>ZNF528</i> overexpression promoted tumor growth and metastasis in mouse xenograft models.<h4>Conclusions</h4><i>ZNF528</i> acts as a novel promoter of NSCLC metastasis, representing a potential prognostic biomarker and therapeutic target.