TRIM25 promotes neuronal ferroptosis in ischemic stroke by suppressing YBX1/H3K4me1/FTH1 axis.

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.