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Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity
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SOD2-Superoxide Metabolic Axis Regulates Mitophagy and Modulates TKIs Sensitivity in Head and Neck Squamous Cell

Wan-Hang Zhou1, Shuo-Jin Huang1, An-Xun Wang1

  • 1Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.

Cancer Science
|March 30, 2026
PubMed

Insights

Superoxide dismutase 2 (SOD2) impacts head and neck cancer (HNSCC) drug response. Targeting SOD2 and its related superoxide metabolism may enhance tyrosine kinase inhibitor (TKI) effectiveness in HNSCC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Superoxide dismutase 2 (SOD2) is linked to head and neck squamous cell carcinoma (HNSCC).
  • The precise role of SOD2 in regulating tumor response to tyrosine kinase inhibitors (TKIs) in HNSCC is not fully understood.
  • Investigating the mitochondrial superoxide-mitophagy pathway offers a potential mechanism.

Purpose of the Study:

  • To determine if SOD2 influences TKI sensitivity in HNSCC via a mitochondrial superoxide-mitophagy axis.
  • To elucidate the mechanistic link between SOD2, mitochondrial function, and mitophagy in HNSCC cells.
  • To evaluate the therapeutic potential of targeting the SOD2-superoxide axis for improving TKI efficacy.

Main Methods:

  • Bioinformatic analysis of SOD2 expression and mitophagy signatures in HNSCC.
  • In vitro functional experiments involving SOD2 silencing and pharmacological modulators (Mito-TEMPO, rotenone).
  • In vivo studies using SOD2 knockout xenograft models treated with TKIs.

Main Results:

  • Elevated SOD2 expression negatively correlated with mitophagy signatures in HNSCC.
  • SOD2 silencing caused mitochondrial superoxide accumulation, impaired function, and activated mitophagy.
  • SOD2 knockdown sensitized HNSCC cells to TKIs, an effect modulated by superoxide levels.
  • SOD2 knockout xenografts showed improved antitumor response to TKIs.

Conclusions:

  • SOD2 is a critical regulator of mitochondrial redox homeostasis and mitophagy in HNSCC.
  • The SOD2-superoxide metabolic axis significantly modulates HNSCC sensitivity to TKIs.
  • Targeting SOD2 and superoxide metabolism presents a promising strategy to enhance TKI efficacy in HNSCC.
Keywords:
anlotinibhead and neck squamous cell carcinomamitophagysuperoxidesuperoxide dismutase 2

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