Collectively, our findings suggest that pathologic downregulation of TSPX in NSCLC, especially in lung adenocarcinoma, results in upregulation of AREG, EREG, FOSL1, MYC, and PLAU, thereby potentiating the EGFR signaling pathway and leading to the initiation and/or exacerbation of cancer development (Figure 6). Here, TSPYL2 is linked to lung adenocarcinoma.