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Emerging dual role of ferroptosis in lung cancer (Review)

  • Authors:
    • Anqi Wu
    • Yingchen Ni
    • Youlang Zhou
    • Jiahai Shi
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    Affiliations: Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
    Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 141
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    Published online on: August 21, 2025
       https://doi.org/10.3892/or.2025.8974
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Abstract

Lung cancer (LC) is the second most frequently diagnosed malignancy worldwide and has the highest mortality rate among all types of cancer. Despite advancements in treatment strategies, the overall survival rate for affected individuals remains low. Ferroptosis, a form of regulated cell death characterized by iron‑dependent lipid peroxidation and accumulation of reactive oxygen species, serves a role in LC. The present review aimed to explore the dual role of ferroptosis in LC, examining both its pathological and therapeutic implications. Ferroptosis contributes to tumor progression, modulates the immune microenvironment and influences treatment resistance. Conversely, it also enhances the efficacy of immunotherapy, increases radiosensitivity and decreases chemotherapy resistance. The present study aimed to summarize the potential of ferroptosis‑based strategies, including the use of nanomaterials and combination therapy, to inform future research and therapeutic approaches.
View Figures

Figure 1

Molecular mechanisms of ferroptosis.
Iron is taken up via TFR1 and released into the labile iron pool
(LIP) through various transporters and reductases. Excess iron can
promote the generation of reactive oxygen species (ROS), which
contribute to lipid peroxidation. Iron export is mediated by
ferroportin (FPN), and its regulation involves hepcidin and other
proteins. Polyunsaturated fatty acids (PUFAs) are activated by
acyl-CoA synthetase (LACS4) and incorporated into phospholipids
(PLs) in the membrane. Lipid peroxidation is initiated by enzymes
like lipoxygenases (LOXs) and can be amplified by the depletion of
GSH) and the inactivation of glutathione peroxidase 4 (GPX4).
CoQ10) and ferroptosis suppressor protein 1 (FSP1) act as
antioxidants to counteract lipid peroxidation. GSH metabolism: The
system Xc-(composed of SLC3A2 and SLC7A11) imports cystine for GSH
synthesis, which is crucial for GPX4 activity. NRF2 regulates
antioxidant responses, while p53 can modulate ferroptosis
sensitivity. Additionally, proteins like NCOA4 mediate
ferritinophagy, releasing iron from ferritin to increase LIP and
promote ferroptosis. TFR, Transferrin receptor; NRAMP, Natural
resistance-associated macrophage protein; ML, Metal transporter
STEAP, Six-transmembrane epithelial antigen of the prostate; HO,
Heme oxygenase; LIP, Labile iron pool; SCL39A14, Solute carrier
family 39 member 14; FPN, Ferroportin; RNF, Ring finger protein;
NCOA, Nuclear receptor coactivator; GSH, Glutathione; NOX, NADPH
oxidase; PUFA, Polyunsaturated fatty acid; LACS, Long-chain
acyl-CoA synthetase; PL, phospholipid; LOX, Lipoxygenase; CoQ,
Coenzyme Q; FSP, Ferroptosis suppressor protein.

Figure 2

Ferroptosis and TIME of lung cancer.
Ferroptotic M1-TAMs) and ferroptotic CD8+ T cells contribute to
tumor progression. Lipid peroxidation (LPO) products like
15-HPETE-PE are released, which may promote an immunosuppressive
environment. Tregs) and M2-TAMs further support tumor growth and
immune evasion. Ferroptotic tumor cells release damage-associated
molecular patterns (DAMPs), which act as ‘find-me’ and ‘eat-me’
signals to recruit and activate immune cells. Natural killer (NK)
cells, dendritic cells (DCs), and M1-TAMs are involved in
recognizing and eliminating tumor cells. CD8+ T cells are activated
by interferon-gamma (IFN-γ) and can recognize tumor cells
expressing PD-L1, with the interaction between PD-1 and PD-L1 being
a key checkpoint in the immune response. TIME, Tumor immune
microenvironment; TAM, Tumor-associated macrophage; Treg,
Regulatory T cell; LPO, Lipid peroxidation; HPETE-PE, Hydroperoxy
eicosatetraenoic acid-phosphatidylethanolamine; DAMP,
damage-associated molecular pattern; NK, Natural killer cell; DC,
Dendritic cell; PD-L, programmed death-ligand.

Figure 3

Ferroptosis and radioresistance. High
expression of SLC3A2/SLC7A11 leads to increased cystine uptake,
which boosts glutathione (GSH) synthesis. GSH then inhibits lipid
peroxidation by activating GPX4, protecting cells from ferroptosis.
Under hypoxia, HIF-1/2 and HILPDA further suppress ferroptosis,
promoting radioresistance. Inhibition of SLC7A11/SLC3A2 (e.g., by
Class I ferroptosis inducers, FINs) reduces cystine uptake and GSH
levels, making cells more susceptible to lipid peroxidation and
ferroptosis. Hypoxia still induces HIF-1/2 and HILPDA, but the
overall effect is increased ferroptosis due to reduced antioxidant
capacity, potentially overcoming radioresistance. SLC3A2, Solute
carrier family 3 member 2; SLC7A11, Solute carrier family≈7 member
11; RT, Radiotherapy; GSH, Glutathione; ROS, Reactive oxygen
species; HIF, Hypoxia-inducible factor; HILPDA, Hypoxia-inducible
lipid droplet-associated protein; PUFA, Polyunsaturated fatty acid;
LPCAT, Lysophosphatidylcholine acyltransferase; ACSL, Acyl-CoA
synthetase long-chain family member; PL, Phospholipid; ALOXS,
Arachidonate lipoxygenase; POR, NADPH-cytochrome P450 reductase;
GPX, Glutathione peroxidase; FIN, Ferroptosis inducer.

Figure 4

Ferroptosis and immunotherapy.
Ionizing radiation generates reactive species, which can induce
ferroptosis in tumor cells. FINs (e.g., Sucfasalazine) target key
metabolic pathways, such as increasing glutathione (GSH) depletion
(via SLC7A11 inhibition) and enhancing reactive oxygen species
(ROS) production (via ACSL4 activation). This leads to lipid
peroxidation and ferroptosis. Ferroptosis is characterized by
decreased GSH, increased ROS, decreased cystine uptake (via system
XC-inhibition), and subsequent cell death. Ferroptotic tumor cells
release DAMPs, which act as ‘find-me’ and ‘eat-me’ signals to
recruit and activate immune cells (e.g., CD8+ T cells, M1
macrophages). This creates an immunogenic microenvironment.
Immunotherapy Synergy: Combining FINs with immunotherapies like
PD-L1 blockers enhances anti-tumor immunity. For example,
radiotherapy-modified platelets (RT-MPs) loaded with ferroptosis
nanoagents (Fe3O4-SAS@PLT) and
TGF-β inhibitors can further boost immune responses by promoting
interferon-gamma (IFN-γ) production and STAT1 signaling. Targeting
Differentiation Plasticity: Ferroptosis can also influence the
differentiation plasticity of immune cells (e.g., macrophages),
shifting them toward a pro-inflammatory (M1) phenotype, which
supports tumor clearance. GSH, Glutathione; SLC7A11, Solute carrier
family 7 member 11; ROS, Reactive oxygen species; FIN, Ferroptosis
inducer; ACSL, Acyl-CoA synthetase long-chain family member; XC,
System Xc-(cystine/glutamate antiporter); RT-MP,
Radiotherapy-modified platelet; SAS@PLT, Sucfasalazine-loaded
platelet; DAMP, Damage-associated molecular pattern; PD-L,
Programmed death-ligand.
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Copy and paste a formatted citation
Spandidos Publications style
Wu A, Ni Y, Zhou Y and Shi J: Emerging dual role of ferroptosis in lung cancer (Review). Oncol Rep 54: 141, 2025.
APA
Wu, A., Ni, Y., Zhou, Y., & Shi, J. (2025). Emerging dual role of ferroptosis in lung cancer (Review). Oncology Reports, 54, 141. https://doi.org/10.3892/or.2025.8974
MLA
Wu, A., Ni, Y., Zhou, Y., Shi, J."Emerging dual role of ferroptosis in lung cancer (Review)". Oncology Reports 54.5 (2025): 141.
Chicago
Wu, A., Ni, Y., Zhou, Y., Shi, J."Emerging dual role of ferroptosis in lung cancer (Review)". Oncology Reports 54, no. 5 (2025): 141. https://doi.org/10.3892/or.2025.8974
Copy and paste a formatted citation
x
Spandidos Publications style
Wu A, Ni Y, Zhou Y and Shi J: Emerging dual role of ferroptosis in lung cancer (Review). Oncol Rep 54: 141, 2025.
APA
Wu, A., Ni, Y., Zhou, Y., & Shi, J. (2025). Emerging dual role of ferroptosis in lung cancer (Review). Oncology Reports, 54, 141. https://doi.org/10.3892/or.2025.8974
MLA
Wu, A., Ni, Y., Zhou, Y., Shi, J."Emerging dual role of ferroptosis in lung cancer (Review)". Oncology Reports 54.5 (2025): 141.
Chicago
Wu, A., Ni, Y., Zhou, Y., Shi, J."Emerging dual role of ferroptosis in lung cancer (Review)". Oncology Reports 54, no. 5 (2025): 141. https://doi.org/10.3892/or.2025.8974
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