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- Title
A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers.
- Authors
Koppula, Pranavi; Lei, Guang; Zhang, Yilei; Yan, Yuelong; Mao, Chao; Kondiparthi, Lavanya; Shi, Jiejun; Liu, Xiaoguang; Horbath, Amber; Das, Molina; Li, Wei; Poyurovsky, Masha V.; Olszewski, Kellen; Gan, Boyi
- Abstract
Targeting ferroptosis, a unique cell death modality triggered by unrestricted lipid peroxidation, in cancer therapy is hindered by our incomplete understanding of ferroptosis mechanisms under specific cancer genetic contexts. KEAP1 (kelch-like ECH associated protein 1) is frequently mutated or inactivated in lung cancers, and KEAP1 mutant lung cancers are refractory to most therapies, including radiotherapy. In this study, we identify ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells. We further show that pharmacological inhibition of the CoQ-FSP1 axis sensitizes KEAP1 deficient lung cancer cells or patient-derived xenograft tumors to radiation through inducing ferroptosis. Together, our study identifies CoQ-FSP1 as a key downstream effector of KEAP1-NRF2 pathway and as a potential therapeutic target for treating KEAP1 mutant lung cancers. KEAP1 mutations are frequently observed in NSCLC and lead to drug resistance. Here, the authors show that KEAP1 mutations in lung cancer cells leads to FSP1 upregulation through NRF2, resulting in ferroptosis resistance and radioresistance.
- Subjects
NUCLEAR factor E2 related factor; LUNG cancer; LIPID peroxidation (Biology)
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-29905-1