2. Academic Validation
  3. C-terminal interleukin 1 alpha (IL-1α) overexpression drives EMT and a vulnerability to ferroptosis in HNSCC

C-terminal interleukin 1 alpha (IL-1α) overexpression drives EMT and a vulnerability to ferroptosis in HNSCC

  • Redox Biol. 2026 Jun:93:104172. doi: 10.1016/j.redox.2026.104172.
Ishrat Nourin Khan 1,  Krishna Awasthi 2,  Ziyu Wang 3,  Nafis Md Irfan 4,  Jay Saepoo 5,  Joan N Whittier 6,  Nurgul Koyuncu 7,  Md Roman Mogal 8,  M M Hasibuzzaman 9,  Shujie Yang 10,  Michael Petronek 11,  Andrean L Simons 12
Affiliations

Affiliations

  • 1 Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA, USA; Iowa City Veterans Affairs Health Care System, Iowa City, IA, USA; Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
  • 2 Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
  • 3 Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
  • 4 Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
  • 5 Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
  • 6 Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
  • 7 Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
  • 8 Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
  • 9 Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA, USA; Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
  • 10 Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
  • 11 Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
  • 12 Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA, USA; Iowa City Veterans Affairs Health Care System, Iowa City, IA, USA; Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: [email protected].
PMID: 42013543 DOI: 10.1016/j.redox.2026.104172
Abstract

High tumor expression of the cytokine interleukin-1 alpha (IL-1α) is associated with an aggressive tumor phenotype and poor clinical outcomes in head and neck squamous cell carcinoma (HNSCC). However, the mechanism behind IL-1α-induced tumor aggressiveness is unclear. The goal of this work is to investigate the biological consequences of increased IL-1α in HNSCC cells. Three IL1A constructs (Full-length, N-terminal, and C-terminal [CT]) were transduced into Cal27 HNSCC cells and validated for IL-1α expression. Differences in cell survival, metabolic profiling, epithelial-to-mesenchymal transition (EMT), oxidative stress parameters and response to therapy were compared among the parental and IL-1α overexpressing cell lines. Overexpression of CT IL-1α (but not the Other constructs) led to increased cell proliferation, membrane fluidity, hydroperoxide production, intracellular iron and lipid peroxidation, EMT changes, and a shift toward glutamate utilization compared to control cell lines. Finally, CT IL-1α cells (but not the Other constructs) were highly sensitive to the Ferroptosis inducer RSL3. Together this work suggests that increased tumor IL-1α expression triggers a shift toward an oxidative and ferroptotic environment, leading to an aggressive tumor phenotype and drug resistance; but also reveals a unique vulnerability to agents that induce Ferroptosis.

Keywords

EGFR; EMT; Ferroptosis; HNSCC; IL-1α.

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