Prion-induced ferroptosis is facilitated by RAC3

Hao Peng, Susanne Pfeiffer, Borys Varynskyi, Marina Qiu, Chanikarn Srinark, Xiang Jin, Xin Zhang, Katie Williams, Bradley R. Groveman, Simote T. Foliaki, Brent Race, Tina Thomas, Chengxuan Chen, Constanze Müller, Krisztina Kovács, Thomas Arzberger, Stefan Momma, Cathryn L. Haigh and Joel A. Schick ()
Additional contact information
Hao Peng: Helmholtz Zentrum Munich
Susanne Pfeiffer: Helmholtz Zentrum Munich
Borys Varynskyi: Helmholtz Zentrum Munich
Marina Qiu: Helmholtz Zentrum Munich
Chanikarn Srinark: Helmholtz Zentrum Munich
Xiang Jin: Hainan Normal University
Xin Zhang: Helmholtz Zentrum Munich
Katie Williams: National Institutes of Health
Bradley R. Groveman: National Institutes of Health
Simote T. Foliaki: National Institutes of Health
Brent Race: National Institutes of Health
Tina Thomas: National Institutes of Health
Chengxuan Chen: Indiana University
Constanze Müller: Helmholtz Zentrum Munich
Krisztina Kovács: Pázmány
Thomas Arzberger: Center for Neuropathology and Prion Research
Stefan Momma: Goethe University
Cathryn L. Haigh: National Institutes of Health
Joel A. Schick: Helmholtz Zentrum Munich

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

Abstract: Abstract Prions are infectious agents that initiate transmissible spongiform encephalopathies, causing devastating neuronal destruction in Creutzfeldt-Jakob and Kuru disease. Rapid cell death depends on presence of the endogenous prion protein PrPC, but its mechanistic contribution to pathogenesis is unclear. Here we investigate the molecular role of PrPC, reactive oxygen species and lipid metabolism in ferroptosis susceptibility, a regulated cell death process characterized by lipid peroxidation. We discover that elevated expression of the cellular prion PrPC creates a relaxed oxidative milieu that favors accumulation of unsaturated long-chain phospholipids responsible for ferroptotic death. This condition is sustained by the luminal protein glutathione peroxidase 8, which detoxifies reactive species produced by protein misfolding. Consequently, both PrPC and infectious Creutzfeldt-Jakob disease (CJD) prions trigger ferroptotic markers and sensitization. This lethality is further enhanced by RAC3, a small GTPase. Depletion of RAC3 is observed solely in pathologically afflicted cortices in CJD patients, revealing a synergistic modulation of lipids and reactive species that drives ferroptosis susceptibility. Together, the results show that PrPC initially suppresses oxidative stress, attenuates cellular defenses, and establishes a systemic vulnerability to the ferroptotic cascade. These results provide insight into the mechanism underlying regulation of ferroptosis in prion diseases and highlight potential therapeutic targets for diseases involving dysregulated cell death processes.

Date: 2025
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DOI: 10.1038/s41467-025-60793-3

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