Ferroptosis-activating metabolite acrolein antagonizes necroptosis and anti-cancer therapeutics
Dysregulated cell death leading to uncontrolled cell proliferation is a hallmark of cancer. Chemotherapy-induced cell death is critical for the success of cancer treatment but this process is impaired by metabolic byproducts. How these byproducts interfere with anti-cancer therapy is unclear. Here, we show that the metabolic byproduct acrolein derived from polyamines, tobacco smoke or fuel combustion, induces ferroptosis independently of ZBP1, while suppressing necroptosis in cancer cells by inhibiting the oligomerization of the necroptosis effector MLKL. Loss of the enzyme SAT1, which contributes to intracellular acrolein production, sensitizes cells to necroptosis. In mice, administration of an acrolein-trapping agent relieves necroptosis blockade and enhances the anti-tumor efficacy of the chemotherapeutic drug cyclophosphamide. Human patients with cancer coupled with a higher cell death activity but a lower expression of genes controlling polyamine metabolism exhibit improved survival. These findings highlight that the removal of metabolic byproducts improves the success of certain chemotherapies.
Authors
- Chirag Patel (ORCID: https://orcid.org/0000-0003-0777-7720)
- Mengmeng Chang
- Si Ming Man (ORCID: https://orcid.org/0000-0002-5079-2857)
- Wonyoung Kim (ORCID: https://orcid.org/0000-0002-2897-9842)
- Minjie Fu (ORCID: https://orcid.org/0000-0002-4649-6545)
- Fenfen Zhang
- Raghvendra Mall (ORCID: https://orcid.org/0000-0003-1779-3150)
- Hyun W. Bae (ORCID: https://orcid.org/0000-0002-6386-344X)
- Rajendra Karki (ORCID: https://orcid.org/0000-0003-4436-9128)
- Jae‐Min Lim (ORCID: https://orcid.org/0000-0002-7153-0194)
- Seyoung Moon (ORCID: https://orcid.org/0009-0004-8665-1871)
- Soyeon Kim (ORCID: https://orcid.org/0009-0001-5918-3759)
- Min Zheng (ORCID: https://orcid.org/0009-0003-9811-4937)
- Seongjun Park (ORCID: https://orcid.org/0000-0002-1981-9628)
- Yeonseo Jang
Institutions
- Australian National University (AU)
- Seoul National University (KR)
- Seoul National University of Education (KR)
- Technology Innovation Institute (AE)
- Biotechnology Research Center (IR)
- Shenzhen Bay Laboratory (CN)
- National University College (PR)
- National Institute on Aging (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-27
- DOI
- https://doi.org/10.1038/s41467-025-60226-1
- Citations
- 11
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 8.87
Funders
- National Research Foundation
- University of Melbourne
- Seoul National University
- National Research Foundation of Korea
- Ministry of Education, Science and Technology
- Ministry of Science and ICT, South Korea