VIB-KU Leuven Researchers Uncover Mechanism of Ferroptosis Activation

In a groundbreaking study published in *Nature Cell Biology*, researchers at the VIB-KU Leuven Center for Cancer Biology have identified a critical interaction between the endoplasmic reticulum (ER) and mitochondria that serves as a pivotal ignition point for ferroptosis, a form of cell death associated with lipid oxidation and iron. This significant discovery sheds light on the mechanisms behind ferroptosis, which has implications for the treatment of various diseases, including cancer and neurodegenerative disorders.

Ferroptosis, characterized by the oxidative damage of phospholipids in cell membranes, has emerged as a vital focus in cancer research due to its role in the death of cancer cells. Traditionally, the initiation site of lipid peroxidation within cells has remained ambiguous. However, the study led by Professor Patrizia Agostinis reveals that the contact sites between the endoplasmic reticulum and mitochondria (EMCSs) are the first cellular membranes susceptible to this oxidative damage.

According to Professor Agostinis, "Our findings show that EMCSs, due to their unique lipid landscape, function as command centers for initiating and propagating lipid peroxidation in cells undergoing ferroptosis." This fundamental knowledge could pave the way for novel therapeutic strategies aimed at enhancing the vulnerability of cancer cells to ferroptosis while potentially mitigating its damaging effects in neurodegenerative diseases.

Utilizing super-resolution live imaging techniques, the research team meticulously tracked the spatiotemporal dynamics of lipid peroxides' formation and dissemination. The findings indicate that upon the onset of lipid peroxidation, EMCSs not only expand but also facilitate the transfer of damaging lipids to mitochondria, leading to increased production of reactive oxygen species (ROS) and subsequent fragmentation of these vital organelles, exacerbating cellular damage.

Maria Livia Sassano, the first author of the study, emphasized the implications of these findings, stating, "Disrupting the physical link between the endoplasmic reticulum and mitochondria significantly reduces the accumulation of harmful lipid peroxides. Conversely, enhancing the connections between these organelles can increase cell death rates."

The research presents a dual potential application: it may inform strategies to enhance ferroptosis in aggressive tumors, such as triple-negative breast cancer (TNBC), which exhibit varying responses to treatment based on their EMCS status. Tumors with a high density of EMCSs are more susceptible to ferroptosis, while those with poor ER-mitochondria contact may resist therapies; however, they can be sensitized by promoting closer interaction between these organelles.

Professor Agostinis remarked, "Our study suggests that the 'EMCS status' could serve as a biomarker for the vulnerability of these tumors to ferroptosis-inducing treatments. Thus, our research not only advances the understanding of ferroptosis but also opens new avenues for targeted cancer therapies."

This research aligns with ongoing efforts to harness ferroptosis in oncology, particularly for treatment-resistant cancer types, while also raising considerations for neurodegenerative conditions where excessive ferroptosis could contribute to pathology. As the scientific community continues to explore the implications of this newly understood mechanism, future investigations may further elucidate the potential for modulating EMCSs to either enhance or inhibit ferroptosis according to therapeutic needs.

Overall, the findings from the VIB-KU Leuven Center for Cancer Biology represent a significant advancement in understanding the cellular mechanisms of ferroptosis, potentially informing future therapeutic strategies that leverage these discoveries to combat cancer and improve patient outcomes.