Objective ·To investigate the expression of protein tyrosine phosphatase receptor type N (PTPRN) in lung adenocarcinoma and its potential molecular mechanisms in promoting lung adenocarcinoma metastasis. Methods ·A highly bone-metastatic A549-BM cell line was established through multiple rounds of intracardiac injection. RNA sequencing (RNA-seq), combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, was performed to identify PTPRN as a key metastasis-related gene. Subsequently, The Cancer Genome Atlas (TCGA) database was utilized to evaluate PTPRN expression in patients with lung adenocarcinoma and its correlation with clinical prognosis. Co-expression analysis based on TCGA data was conducted to identify and analyze key genes co-expressed with PTPRN. Small interfering RNA (siRNA) targeting PTPRN (siPTPRN) was transfected into A549-BM cells, and Transwell assays were performed to assess its effects on cell migration and invasion. Western blotting was used to detect the expression of epithelial-mesenchymal transition (EMT)-related proteins and the activation of the PI3K-AKT signaling pathway. siPTPRN-transfected A549-BM cells were injected into a mouse model via intracardiac injection, and in vivo metastasis was assessed. Additionally, multiple database analyses were integrated to predict BCL6 as an upstream transcription factor of PTPRN, and siBCL6 transfection experiments were performed to validate the regulatory effect of BCL6 on PTPRN expression. Results ·RNA-seq and GO/KEGG enrichment analyses demonstrated that PTPRN was significantly upregulated in highly metastatic A549-BM cells and enriched in metastasis-associated pathways, including the PI3K-AKT signaling pathway and extracellular matrix (ECM)-receptor interactions. Analysis of the TCGA database further confirmed that PTPRN was highly expressed in lung adenocarcinoma patients and significantly associated with poor prognosis. Co-expression analysis based on TCGA data, combined with GO/KEGG enrichment analyses, revealed that PTPRN-associated genes were mainly enriched in biological processes such as neural signaling, endocrine regulation, cell communication, and ECM-receptor interactions. In vitro experiments demonstrated that siPTPRN transfection significantly inhibited the migration and invasion of A549-BM cells, accompanied by downregulation of EMT-related proteins and reduced activation of the PI3K-AKT signaling pathway. In vivo experiments further showed that PTPRN knockdown markedly suppressed the metastatic potential of A549-BM cells, confirming its pro-metastatic role. Additionally, siBCL6 transfection experiments demonstrated that BCL6 knockdown upregulated PTPRN expression. Conclusion ·PTPRN is highly expressed in lung adenocarcinoma tissues and promotes tumor cell migration and metastasis by enhancing EMT and activating the PI3K-AKT signaling pathway. High PTPRN expression is significantly correlated with poor prognosis in lung adenocarcinoma patients, while PTPRN enhances lung adenocarcinoma cell invasiveness and metastatic potential. BCL6 may act as an upstream transcriptional regulator of PTPRN, influencing its expression levels.