Targeting dual-specificity phosphatase 23 to overcome chemoresistance and stem cell-like behavior in non-small cell lung cancer cells.

Chemoresistance remains a significant challenge in the treatment of non-small cell lung cancer (NSCLC) and is often associated with poor clinical outcomes. This resistance is closely linked to cancer stem cell (CSC)-like properties, such as the ability to evade anoikis. In this study, we identify dual-specificity phosphatase 23 (DUSP23) as a critical regulator of CSC-like traits and chemoresistance. DUSP23 expression was significantly elevated in cell clusters grown under ultra-low adhesion conditions that mimic CSC-promoting environments. DUSP23 knockdown impaired cluster formation, and suppressed the expression of SOX2, a representative marker for CSC-like property, and lung tumorigenesis in vivo. In cisplatin-resistant NSCLC cells, DUSP23 knockdown further decreased invasive behavior and induced apoptosis. Mechanistically, DUSP23 promoted STAT3 phosphorylation, thereby enhancing SOX2 transcription in cisplatin-resistant cells. Clinically, a DUSP23–SOX2 target gene signature stratified patients into high- and low-risk groups, with high-risk patients showing significantly shorter overall and disease-free survival. Collectively, our findings indicate that DUSP23 plays a central role in maintaining CSC-like properties and chemoresistance through the regulation of SOX2. Targeting DUSP23 may provide a novel therapeutic approach to overcome treatment resistance and improve outcomes for patients with NSCLC.