Unveiling the intricate mechanisms behind oxysterol-induced cell death

Oxysterols are a class of molecules derived from cholesterol via oxidation or as byproducts of cholesterol synthesis. Despite their relatively low concentration within our bodies, oxysterols are known to play many important biological roles, acting as transcriptional regulators, precursors for bile acid, and key players in brain development.

On the flip side, some pathologies are associated with imbalances in oxysterols. In particular, 25-hydroxycholesterol (25-OHC) has been shown to contribute to arteriosclerosis, cancer development, central nervous system disorders, dysregulated immune responses, and macular degeneration. Despite substantial efforts, the molecular mechanisms by which 25-OHC affects glial cells in diseases like amyotrophic lateral sclerosis (ALS) remain unclear.

Against this backdrop, a research team led by Professor Yasuomi Urano and Professor Noriko Noguchi from the Graduate School of Life and Medical Sciences, Doshisha University, Japan, explored the intricate roles of 25-OHC in inducing cell death, particularly in glial cells. Their paper was made available online on January 6, 2025, and was published in Volume 228 of Free Radical Biology and Medicine on February 16, 2025.

The researchers sought to clarify how 25-OHC contributes to cell death in Schwann cell cultures, which are essential supporting cells in the nervous system. Through extensive experimentation, they revealed that 25-OHC induces a specific type of cell death called ferroptosis—an iron-dependent process characterized by the accumulation of toxic fatty molecules within cells. “While 25-OHC is thought to be mainly associated with inducing apoptosis in various cell types, our findings highlight the importance of considering ferroptosis as a potential cell death mechanism triggered by a similar concentration of 25-OHC,” explains Urano.

More specifically, the team identified two key mechanisms for 25-OHC-induced ferroptosis. First, 25-OHC inhibits important cellular pathways involving the processing of SREBPs (or Sterol Regulatory Element-Binding Proteins), which normally help maintain lipid homeostasis and protect cells from metabolic imbalance. Second, it disrupts the cell’s natural antioxidant systems by reducing levels of a crucial protective enzyme called glutathione peroxidase 4, leading to redox imbalances.

Interestingly, the researchers revealed that even at concentrations too low to directly cause cell death, exposure to 25-OHC makes cells more susceptible to ferroptosis. This result has significant implications for understanding how diseases like ALS might progress, as even modest elevations in 25-OHC levels could contribute to long-term cellular damage.

Together, the findings suggest several promising directions for future investigation, including the development of drugs that could block ferroptosis or prevent 25-OHC accumulation. Alternatively, one could also leverage oxysterols to make tumor cells more vulnerable. “Considering the promising potential of cancer therapy with ferroptosis inducers, 25-OHC is expected to enhance the efficacy of ferroptosis inducers as anticancer agents,” highlights Urano. Additionally, measuring 25-OHC levels could potentially serve as a biomarker for the early detection of various diseases, though this would require further validation.

Overall, this study represents a significant step forward in understanding how oxysterols contribute to both regular and pathological processes. With any luck, these newfound insights will let us develop innovative therapeutic and diagnostic strategies for challenging conditions.

About Professor Yasuomi Urano from Doshisha University, Japan
Professor Yasuomi Urano is a distinguished researcher at Doshisha University's Graduate School of Life and Medical Sciences. He joined Doshisha University in 2009 as an Assistant Professor and was promoted to Associate Professor in 2018 and to Full Professor in 2024. His research focuses on cell death mechanisms, oxysterols, neuroscience, and lipid metabolism, with particular emphasis on cholesterols and their role in neuropathologies. He has published over peer-reviewed 40 research papers on these topics.

About Professor Noriko Noguchi from Doshisha University, Japan
Dr. Noriko Noguchi is a Professor at the Graduate School of Life and Medical Sciences at Doshisha University. She received her Ph.D. from the University of Tsukuba, Japan, in 1987. Her research focuses on elucidating the molecular mechanisms of lifestyle-related diseases such as Alzheimer's disease, diabetes, and cancer, with a particular emphasis on oxidative stress. She has more than 38 years of experience as a researcher and has about 200 publications in peer-reviewed international journals.  

Funding information
This work was supported in part by JSPS KAKENHI Grant-in-Aid for Scientific Research (C) 19K07093 and 23K10902.

Media contact:
Organization for Research Initiatives & Development
Doshisha University
Kyotanabe, Kyoto 610-0394, Japan
E-mail: jt-ura@mail.doshisha.ac.jp

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