SOX2 transactivates NRF2 to promote carboplatin resistance in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) remains a major therapeutic challenge because of its pronounced resistance to chemotherapy, particularly carboplatin. In this study, we investigate the role of SOX2, a lineage-survival oncogene, in mediating carboplatin resistance in LUSC. We demonstrate that SOX2 is highly expressed in LUSC and is significantly associated with poor prognosis. Our results show that SOX2 directly transactivates the expression of NRF2, a master regulator of cellular redox homeostasis, thereby increasing glutathione (GSH) synthesis and protecting cells from carboplatin-induced oxidative stress. Pharmacological or genetic inhibition of NRF2 effectively abrogates SOX2-mediated carboplatin resistance both in vitro and in vivo, resensitizing LUSC cells to chemotherapy. These findings highlight SOX2 as a critical redox regulator that modulates NRF2 signaling to promote carboplatin resistance in LUSC. The identification of the SOX2-NRF2 axis as a potential therapeutic target suggests that NRF2 inhibition may represent a promising strategy to overcome chemoresistance in LUSC.