️ 56: Neuronal Immunoproteasome — A Metabolic Trigger for Ferroptotic Neurodegeneration in Multiple Sclerosis

️ Episode 56: Neuronal Immunoproteasome — A Metabolic Trigger for Ferroptotic Neurodegeneration in Multiple Sclerosis In this episode of Base by Base, we examine the transformative findings of Woo et al. (2025) in Cell, revealing how inflammation reshapes neuronal proteostasis. Under interferon-γ–driven stress, neurons incorporate the immunoproteasome subunit PSMB8 into their core proteasome, profoundly impairing catalytic function. This shift undermines the degradation of the glycolytic regulator PFKFB3, setting off a cascade of metabolic reprogramming that favors glycolysis over the pentose phosphate pathway, depletes antioxidant defenses, and precipitates oxidative injury. Key highlights: the study demonstrates that interferon-γ–induced PSMB8 expression in neurons leads to a marked reduction in β5 catalytic activity, resulting in PFKFB3 accumulation and a metabolic switch that elevates reactive oxygen species and sensitizes cells to glutamate-induced excitotoxicity and ferroptosis. Neuron-specific genetic deletion of PSMB8 or systemic treatment with the immunoproteasome inhibitor ONX-0914 restores proteasome balance, prevents PFKFB3 buildup, replenishes glutathione pools, and confers robust neuroprotection in mouse models of multiple sclerosis. Parallel experiments targeting PFKFB3 with the small-molecule inhibitor Pfk-158 further validate the immunoproteasome–PFKFB3 axis as a therapeutic gateway. Conclusion: this work positions the neuronal immunoproteasome as a critical nexus linking neuroinflammation to metabolic collapse and ferroptotic cell death, and proposes PSMB8 and PFKFB3 inhibition as promising strategies to safeguard neurons in multiple sclerosis and potentially other neurodegenerative disorders. Reference: Woo, M. S., Brand, J., Bal, L. C., Moritz, M., Walkenhorst, M., Vieira, V., Ipenberg, I., et al. (2025). The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis. Cell, 188, 1–19. https://doi.org/10.1016/j.cell.2025.05.029 License: This episode is based on an open access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/