The EGR1/ZFP36 axis governs glycosphingolipid metabolic reprogramming in monocyte-derived macrophages in...

Guillain-Barré syndrome (GBS) is an immune-mediated demyelinating disorder of peripheral nerves with an unclear pathogenesis. This study integrated GBS clinical single-cell data with EAN model transcriptome data, establishing in vivo and in vitro experimental systems to reveal, for the first time, a novel mechanism involving EGR1-ZFP36 and its mediated metabolic reprogramming in GBS pathogenesis. Findings indicated that the transcription factor EGR1 and its predicted target gene ZFP36 were downregulated in both GBS patients and EAN rats. Molecular interaction validation confirmed that EGR1 directly bound to and activated the transcription of ZFP36. Transcriptomic and metabolomic analyses revealed that the EGR1/ZFP36 axis specifically drove macrophage reprogramming toward a glycosphingolipid metabolism-active state. Functionally, EGR1 overexpression promoted the expression of key glycosphingolipid metabolism genes (HEXA, HEXB) by upregulating ZFP36, thereby facilitating polarization toward the anti-inflammatory M2 phenotype. Animal experiments further demonstrated that EGR1 overexpression improved motor function and ameliorated myelin damage in the EAN model, with this protective effect being mediated by ZFP36. Collectively, this study reveals that EGR1 drives glycosphingolipid metabolic reprogramming in monocyte-derived macrophages by transcriptionally activating ZFP36, thereby regulating cellular polarization and participating in the demyelination process of GBS. This discovery not only provides a novel perspective on understanding the immunometabolic mechanisms of GBS but also lays a theoretical foundation for potential therapeutic strategies targeting the EGR1-ZFP36-glycosphingolipid metabolism axis.