Ferroptosis-activating metabolite acrolein antagonizes necroptosis and anti-cancer therapeutics

Hyun Bae, Seonghyun Moon, Mengmeng Chang, Fenfen Zhang, Yeonseo Jang, Wonyoung Kim, Soyeon Kim, Minjie Fu, Jaemin Lim, Seongjun Park, Chirag N. Patel, Raghvendra Mall, Min Zheng, Si Ming Man () and Rajendra Karki ()
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Hyun Bae: Seoul National University
Seonghyun Moon: Seoul National University
Mengmeng Chang: Shenzhen Bay Laboratory
Fenfen Zhang: Shenzhen Bay Laboratory
Yeonseo Jang: Seoul National University
Wonyoung Kim: Seoul National University
Soyeon Kim: Seoul National University
Minjie Fu: Seoul National University
Jaemin Lim: Bertis Inc.
Seongjun Park: Bertis Inc.
Chirag N. Patel: Technology Innovation Institute
Raghvendra Mall: Technology Innovation Institute
Min Zheng: Shenzhen Bay Laboratory
Si Ming Man: The Australian National University
Rajendra Karki: Seoul National University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60226-1

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