The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression
Open accessAbstract
Ferroptosis, a form of regulated cell death caused by lipid peroxidation, was recently identified as a natural tumor suppression mechanism. Here, we show that ionizing radiation (IR) induces ferroptosis in cancer cells. Mechanistically, IR induces not only reactive oxygen species (ROS) but also the expression of ACSL4, a lipid metabolism enzyme required for ferroptosis, resulting in elevated lipid peroxidation and ferroptosis. ACSL4 ablation largely abolishes IR-induced ferroptosis and promotes radioresistance. IR also induces the expression of ferroptosis inhibitors, including SLC7A11 and GPX4, as an adaptive response. IR- or KEAP1 deficiency-induced SLC7A11 expression promotes radioresistance through inhibiting ferroptosis. Inactivating SLC7A11 or GPX4 with ferroptosis inducers (FINs) sensitizes radioresistant cancer cells and xenograft tumors to IR. Furthermore, radiotherapy induces ferroptosis in cancer patients, and increased ferroptosis correlates with better response and longer survival to radiotherapy in cancer patients. Our study reveals a previously unrecognized link between IR and ferroptosis and indicates that further exploration of the combination of radiotherapy and FINs in cancer treatment is warranted.
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Ionizing radiation can promote ferroptosis by inducing ROS production but also induce upregulation of SLC7A11 and GPX4, resulting in negative feedback and radiation resistance.
“Ionizing radiation (IR) can not only promote ferroptosis by inducing reactive oxygen species (ROS) production but also induce the upregulation of SLC7A11 and GPX4 expression, resulting in negative feedback, ultimately leading to radiation resistance”
From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [12]
Combination of ferroptosis inducers significantly increases the killing effect of IR on tumor cells.
“the combination of ferroptosis inducers significantly increases the killing effect of IR on tumor cells12.”
From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [12]
Inhibition of SLC7A11 and GPX4 can promote ferroptosis and sensitize radiation-resistant cells to IR.
“The inhibition of SLC7A11 and GPX4 can promote ferroptosis and sensitize radiation-resistant cells to IR12.”
From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [12]
IR promotes lipid peroxidation and ferroptosis by inducing ROS production and upregulating ACSL4 expression; however, it also upregulates the ferroptosis-inhibiting proteins SLC7A11 and GPX4 to counteract ferroptosis.
“IR promotes lipid peroxidation and ferroptosis by inducing ROS production and upregulating ACSL4 expression; however, it also upregulates the expression of the ferroptosis-inhibiting proteins SLC7A11 and GPX4 to counteract ferroptosis12.”
From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [12]
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- Authors
- Lei, G., Zhang, Y., Koppula, P., Liu, X., Zhang, J., Lin, S. H., Ajani, J. A., Xiao, Q., Liao, Z., Wang, H., & Gan, B.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Central South University (CN)
- Corresponding author
- Wang, Hui
- Gan, Boyi
- ORCID
- Venue
- Cell Research
- Published
- 2020-01-16
- Volume
- 30
- Issue
- 2
- Pages
- 146-162
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC7015061
- OpenAlex
- W3000233190
- Cited by
- 1,318
- References
- 12
- Citations by year
- 2026: 155 · 2025: 247 · 2024: 295 · 2023: 251 · 2022: 210 · 2021: 118 · 2020: 42
- FWCI
- 87.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (RP170067)
- University of Texas Health Science Center at Houston
- University of Texas MD Anderson Cancer Center (RP170067)
- National Cancer Institute (P30CA016672)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
- Keywords
- ferroptosis, ionizing radiation, radioresistance (biology), tumor suppression, ACSL4, lipid peroxidation, reactive oxygen species, SLC7A11, GPX4, Keap1, ferroptosis inducers, radiotherapy response, cancer cell death
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Ferroptosis, Long-Chain-Fatty-Acid-CoA Ligase, Animals, Coenzyme A Ligases, DNA Damage, DNA Repair, Glutathione Peroxidase, Humans, Neoplasms, Radiation Tolerance, Radiation, Ionizing, Up-Regulation, Mice, SCID, Mice, Inbred NOD, Amino Acid Transport System y+, Cell Line, Tumor
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