SOX2 Inhibits Cuproptosis to Affect Cisplatin Resistance in Non‐Small Cell Lung Cancer by Activating the Wnt/ ATP7B Signaling Pathway

ABSTRACT Cisplatin (CDDP) resistance constitutes the principal clinical challenge in the treatment of advanced non‐small cell lung cancers (NSCLC). Disturbances in copper metabolism are closely linked with tumor drug resistance. SOX2, a pivotal stemness transcription factor (TF), holds an important role in chemotherapy resistance. However, whether it influences CDDP resistance by modulating cuproptosis remains unknown. SOX2 level was tested by qPCR and WB, and ATP7B level was evaluated by WB and flow cytometry. The oligomerization levels of FDX1, LIAS, and DLAT, together with Cu 2+ levels, were determined by WB, confocal microscopy, and a Cu 2+ colorimetric assay kit. The proliferation and apoptosis of NSCLC drug‐resistant cells were assessed with CCK‐8 and flow cytometry. SOX2 was significantly up‐regulated in CDDP‐resistant NSCLC cells, accompanied by decreased cuproptosis sensitivity. Silencing SOX2 in CDDP‐resistant cells increased cuproptosis sensitivity and apoptosis rate and reduced cell viability. These effects of SOX2 silencing on CDDP resistance in NSCLC cells were reversed by the cuproptosis inhibitor TTM. SOX2 up‐regulated ATP7B by activating the Wnt/β‐catenin signaling pathway. Silencing ATP7B or treatment with the Wnt pathway inhibitor LF3 attenuated SOX2 overexpression‐induced promoting effect on CDDP resistance and suppressive effect on cuproptosis in NSCLC. In summary, this study reveals a novel mechanism wherein SOX2 activates the Wnt/β‐catenin signaling pathway to upregulate ATP7B expression, thereby suppressing cuproptosis and ultimately driving cisplatin resistance in NSCLC. These findings provide potential therapeutic targets for reversing chemoresistance in NSCLC.