2. Academic Validation
  3. Ferroptosis-activating metabolite acrolein antagonizes necroptosis and anti-cancer therapeutics

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

  • Nat Commun. 2025 May 27;16(1):4919. doi: 10.1038/s41467-025-60226-1.
Hyun Bae # 1,  Seonghyun Moon # 1 2,  Mengmeng Chang 3,  Fenfen Zhang 3,  Yeonseo Jang 1,  Wonyoung Kim 1,  Soyeon Kim 1,  Minjie Fu 1,  Jaemin Lim 4,  Seongjun Park 4,  Chirag N Patel 5 6,  Raghvendra Mall 5,  Min Zheng 3,  Si Ming Man 7,  Rajendra Karki 8
Affiliations

Affiliations

  • 1 Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
  • 2 Department of Biology Education, College of Education, Seoul National University, Seoul, Republic of Korea.
  • 3 Institute of infectious diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China.
  • 4 Bertis Inc., Gyeonggi-do, Republic of Korea.
  • 5 Biotechnology Research Center, Technology Innovation Institute, Abu Dhabi, UAE.
  • 6 Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA.
  • 7 Division of Immunology and Infectious Diseases, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia. siming.man@anu.edu.au.
  • 8 Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea. rkarki@snu.ac.kr.
  • # Contributed equally.
PMID: 40425585 DOI: 10.1038/s41467-025-60226-1
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.

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