ArticleThe journal of headache and pain2026
CB2R-mediated GPX4 stabilization: a new avenue for treating cognitive impairment in elderly migraine patients.
Article in The journal of headache and pain, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
1 citing paper in PubMed, 1 synthesis or guideline pooled it.
- The mechanism of different microglial receptors mediating central inflammation in chronic migraine: a meta-analysis.The journal of headache and pain · 2026Pooled it
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
Migraine is frequently associated with cognitive impairment, a pathology linked to microglial dysfunction and neuroinflammation. Ferroptosis, a form of iron-dependent lipid peroxidation, driven by the depletion of glutathione peroxidase 4 (GPX4), is increasingly implicated in neurodegenerative processes. This study investigates the protective role of cannabinoid receptor type 2 (CB2R) activation against migraine-associated cognitive deficits by modulating microglial ferroptosis. We demonstrate that CB2R activation, via its agonist JWH133, significantly ameliorates cognitive impairment and synaptic damage in a nitroglycerin-induced migraine model. Mechanistically, JWH133 suppresses microglial ferroptosis by stabilizing GPX4. Our findings reveal that in inflammatory conditions, the E3 ubiquitin ligase Tripartite Motif Containing 33 (TRIM33) mediates the K63-linked polyubiquitination of GPX4, marking it for breakdown via autophagy, a cellular process that degrades unwanted proteins through lysosomes. CB2R activation inhibits TRIM33-GPX4 interaction and subsequent K63-linked ubiquitination, thereby preventing GPX4 degradation and restoring its anti-lipid peroxidation function. This stabilization of GPX4 mitigates mitochondrial dysfunction and lipid peroxidation, as evidenced by lipidomics and mitochondrial assays. Collectively, our study uncovers a novel CB2R-TRIM33-K63 ubiquitination-autophagy axis that critically regulates GPX4 stability and microglial ferroptosis. Targeting this pathway offers a promising therapeutic strategy for mitigating migraine-associated cognitive impairment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.