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TRIM25 promotes neuronal ferroptosis in ischemic stroke by suppressing YBX1/H3K4me1/FTH1 axis
Kaimin Zeng1, Jing-Jing Peng1, Ziwei Lan1
1Neurology Department, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China.
Background:
Ferroptosis impairs neurological function in ischemic stroke (IS). This study elucidated the mechanism by which Tripartite motif 25 (TRIM25) promotes neuronal ferroptosis during IS.
Methods:
CCK-8 detected cell viability. Flow cytometry and corresponding kits quantified ferroptosis-related parameters. TTC staining determined cerebral infarct volume. Neurological impairment was assessed using neurological deficit scoring and Nissl staining. RT-qPCR, Western blot, and immunohistochemistry assessed the mRNA and protein expression. Co-IP analyzed the ubiquitinated level of Y-box binding protein 1 (YBX1) and the interaction between TRIM25 and YBX1. ChIP assessed the binding of YBX1 and H3K4me1 at the Ferritin heavy chain 1 (FTH1) promoter. Peptide pull-down assessed the interaction between YBX1 and H3K4me1.
Results:
TRIM25 promoted neuronal ferroptosis in IS. TRIM25 promoted YBX1 ubiquitination and degradation. YBX1 knockdown counteracted the suppressive outcome of TRIM25 depletion on OGD/R-induced ferroptosis. YBX1 upregulated FTH1 by recognizing H3K4me1 enrichment at the FTH1 promoter, thus inhibiting OGD/R-induced neuronal ferroptosis. In vivo, TRIM25 knockdown attenuated MCAO/R-induced brain injury via YBX1 upregulation.
Conclusion:
TRIM25 induces YBX1 ubiquitination and degradation, impairing YBX1-dependent H3K4me1 enrichment at the FTH1 promoter to downregulate FTH1, thereby promoting neuronal ferroptosis in IS.
