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

Hanfei Gao1, Chaomei Li2, Jie Sun1

  • 1Department of Cardiothoracic Surgery, School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China.

Acta Biochimica Et Biophysica Sinica
|December 6, 2025
PubMed

Insights

SOX2 promotes carboplatin resistance in lung squamous cell carcinoma (LUSC) by activating NRF2, a key regulator of cellular defense. Inhibiting NRF2 resensitizes LUSC to chemotherapy, offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Lung squamous cell carcinoma (LUSC) exhibits significant resistance to chemotherapy, particularly carboplatin.
  • SOX2, an oncogene, is implicated in various cancers and its role in LUSC chemoresistance is under investigation.

Purpose of the Study:

  • To investigate the role of SOX2 in mediating carboplatin resistance in LUSC.
  • To elucidate the molecular mechanisms underlying SOX2-driven chemoresistance.
  • To identify potential therapeutic targets for overcoming carboplatin resistance in LUSC.

Main Methods:

  • Expression analysis of SOX2 in LUSC tissues.
  • Investigating the regulatory relationship between SOX2 and NRF2.
  • Assessing the impact of SOX2 and NRF2 modulation on carboplatin sensitivity in vitro and in vivo.
  • Measuring glutathione (GSH) synthesis and oxidative stress levels.

Main Results:

  • SOX2 is highly expressed in LUSC and correlates with poor prognosis.
  • SOX2 directly upregulates NRF2 expression, enhancing glutathione synthesis and protecting against carboplatin-induced oxidative stress.
  • Inhibition of NRF2 (pharmacological or genetic) reverses SOX2-mediated carboplatin resistance in LUSC models.

Conclusions:

  • SOX2 acts as a critical redox regulator in LUSC by modulating the NRF2 pathway.
  • The SOX2-NRF2 axis is a key driver of carboplatin resistance in LUSC.
  • Targeting NRF2 presents a promising therapeutic strategy to enhance chemotherapy efficacy in LUSC patients.
Keywords:
LUSCNRF2ROSSOX2carboplatin resistance

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