56: When the Immunoproteasome Turns Toxic: PSMB8, PFKFB3 and Ferroptosis in MS

Woo et al et al., Cell - This study shows that interferon-driven induction of the immunoproteasome subunit PSMB8 in neurons reduces proteasome β5 catalytic activity, causing accumulation of the glycolytic regulator PFKFB3. PFKFB3 accumulation shifts neurons from the pentose phosphate pathway to glycolysis, lowering NADPH/GSH, increasing ROS and lipid peroxidation, and sensitizing neurons to ferroptosis. Neuron-specific genetic deletion or pharmacologic inhibition of PSMB8 or PFKFB3 protected neurons in vitro and in mouse EAE models, highlighting new neuroprotective strategies for MS. Key terms: immunoproteasome, PSMB8, PFKFB3, ferroptosis, multiple sclerosis. Study Highlights:IFNγ induces neuronal PSMB8 expression in MS and EAE and PSMB8 replaces PSMB5 in the proteasome. PSMB8 incorporation decreases proteasomal β5 catalytic activity, impairing degradation of PFKFB3 and leading to its accumulation. PFKFB3 drives a metabolic switch to glycolysis, reduces PPP-derived NADPH and GSH, increases ROS and lipid peroxidation, and increases susceptibility to ferroptosis. Targeting PSMB8 or PFKFB3 genetically or pharmacologically protects neurons and reduces neurodegeneration in EAE. Conclusion:IFN-driven neuronal PSMB8 expression impairs proteasomal degradation, stabilizes PFKFB3 and triggers a glycolytic shift that depletes antioxidant defenses and promotes ferroptotic neurodegeneration, and PSMB8/PFKFB3 inhibition offers a promising neuron-targeted neuroprotective approach in MS. Music:Enjoy the music based on this article at the end of the episode. Article title:The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis First author:Woo et al Journal:Cell DOI:10.1016/j.cell.2025.05.029 Reference:Woo et al., 2025, Cell 188, 4567–4585. 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/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/the-immunoproteasome-disturbs-neuronal-metabolism-and-drives-neurodegeneration-in-multiple-sclerosis QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-26. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited transcript sections describing IFN-γ–driven neuronal immunoproteasome remodeling (PSMB8), the proteasome shift affecting PFKFB3, PPP-to-glycolysis metabolic reprogramming, NADPH and glutathione depletion, ferroptosis susceptibility, and in vivo interventions (neuron-specific Psmb8 deletion; ONX-0914; Pfkfb3 inh- transcript topics: IFN-γ–driven neuronal immunoproteasome remodeling (PSMB8); Proteasome core composition: 20S core vs immunoproteasome; PFKFB3 accumulation and PPP-to-glycolysis shift; NADPH and GSH depletion; ROS and lipid peroxidation; Ferroptosis as a neuronal death mechanism; In vivo interventions: neuronal Psmb8 deletion; ONX-0914; Pfkfb3 inhibition QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 5- claims flagged for review: 0- metadata checks passed: 4-...