A study that elucidated the pathogenesis of prion diseases—which have a fatality rate approaching 100% and currently have no effective treatments—has been published and is drawing international attention.

The research team led by Professor Byung-Hun Jeong of Jeonbuk National University (JBNU) Institute for Molecular Biology and Genetics reported that ferroptosis acts as a key mechanism of neuronal cell death in prion diseases and proposed the potential of therapeutic strategies targeting this process. Ferroptosis is an oxidative stress–based form of cell death driven by iron-dependent lipid peroxidation.

Prion diseases are fatal neurodegenerative disorders caused by accumulation of abnormally folded prion protein (PrPSc) in the brain. Representative examples include human Creutzfeldt–Jakob disease (CJD) and bovine spongiform encephalopathy (BSE). The diseases progress rapidly and have high mortality, and to date no effective treatments have been developed.

The team conducted an integrated analysis of brain tissues from human sporadic CJD (sCJD) patients, a prion-infected mouse model (ME7), and a cell model (PrP106-126-treated SH-SY5Y cells) to systematically identify ferroptosis-associated changes. They found characteristic biochemical alterations of ferroptosis in sCJD patient brains, including a significant decrease in expression of the antioxidant enzyme GPX4 and an increase in malondialdehyde (MDA), a marker of lipid peroxidation.

At the cellular level, treatment with prion peptide induced core indicators of ferroptosis—an increase in reactive oxygen species (ROS), accumulation of Fe2+, and depletion of glutathione—demonstrating a mechanism distinct from previously described modes of cell death.

Notably, treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) restored neuronal survival and significantly reduced oxidative stress and lipid peroxidation. This indicates that prion-induced neurotoxicity can be modulated via the ferroptosis pathway.

A similar pattern was observed in the animal model. In ME7-infected mice, expression of GPX4 and SLC7A11 was reduced, while oxidative stress and neuronal damage increased, revealing pronounced ferroptosis-related pathological changes. Gene expression analysis also identified alterations in 130 ferroptosis-related genes in sCJD patients, supporting ferroptosis as a major pathophysiological axis in prion diseases.

The findings were published in the latest issue of the international life-science journal Redox Biology (IF 11.9) and have been featured in the Biological Research Information Center (BRIC) series "Korea's Shining People (Hanbit-sa)," recognizing the study's excellence.

Professor Byung-Hun Jeong said, "This is a systematic study that elucidates the mechanism of neuronal cell death in prion diseases from the perspective of ferroptosis. It is significant because it proposes the possibility of developing therapies that target ferroptosis." He added, "In the future, development of related drugs may be expected to suppress disease progression and protect neurons in prion diseases."

This research was supported by the National Research Foundation of Korea's Mid-Career Researcher Support Program and the Creative·Pioneering University-based Research Center Support Program, and was conducted based on research infrastructure provided by the JBNU Institute for Molecular Biology and Genetics and the Zoonosis Core Research Support Center.