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IER3 promotes non-small cell lung cancer malignancy by suppressing ferroptosis via the AKT/GSK3β/NRF2 pathway

Yi Chen1, Zhaoyu Liu2, Zesen Mai2

  • 1Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510000, China; Research Center of Cancer Diagnosis and Therapy, Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China.

Free Radical Biology & Medicine
|January 25, 2026
PubMed

Insights

Immediate Early Response 3 (IER3) drives non-small cell lung cancer (NSCLC) by suppressing ferroptosis, a cell death pathway. Targeting IER3 may improve NSCLC treatment and prognosis by re-sensitizing tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • Non-small cell lung cancer (NSCLC) presents significant therapeutic challenges due to resistance and recurrence.
  • Ferroptosis, a regulated cell death, offers a potential strategy against cancer drug resistance, but its mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the role of Immediate Early Response 3 (IER3) in NSCLC progression and its connection to ferroptosis.
  • To elucidate the molecular mechanisms by which IER3 influences ferroptosis and NSCLC malignancy.

Main Methods:

  • Utilized IER3-overexpressing and knockout NSCLC cell models (A549, H1299).
  • Assessed cell proliferation, migration, invasion, and ferroptosis markers.
  • Investigated the AKT/GSK3β/NRF2 signaling pathway and downstream gene expression.
  • Employed ferroptosis inhibitors (Fer-1) and rescue assays with NRF2 or AKT/GSK3β modulation.

Main Results:

  • IER3 is upregulated in NSCLC, correlating with advanced stage and poor prognosis.
  • IER3 overexpression suppressed ferroptosis, promoting NSCLC proliferation, migration, and invasion.
  • IER3 knockout induced ferroptosis, reducing NSCLC malignancy, an effect reversed by Fer-1.
  • Mechanistically, IER3 sustained AKT phosphorylation, inactivating GSK3β, which stabilized NRF2, leading to ferroptosis suppression.
  • Low-IER3 NSCLC tumors showed increased sensitivity to targeted therapies.

Conclusions:

  • IER3 acts as an oncogenic driver in NSCLC by inhibiting ferroptosis through the AKT/GSK3β/NRF2 pathway.
  • IER3 is a potential prognostic biomarker and therapeutic target for improving NSCLC outcomes.
  • Targeting IER3 may re-sensitize NSCLC to existing therapies by reactivating ferroptosis.
Keywords:
AKT/GSK3β/NRF2FerroptosisIER3MalignancyNSCLC

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