Erk5-mediated microglial ferroptosis drives ischemic white matter damage via the Nfatc4–Clptm1l axis

Ischemic white matter damage is a significant pathological feature of chronic cerebral hypoperfusion, leading to cognitive impairments. However, the underlying molecular mechanisms remain poorly understood. In this study, we identify a causal association between genetically predicted extracellular signal-regulated kinase 5 (ERK5) expression and higher white matter hyperintensity volume through druggable target screening, suggesting its potential as a therapeutic target for white matter damage. Using different animal models of white matter damage, we show that Erk5 expression is significantly upregulated in microglia following both ischemic and demyelinating injury, correlating with the severity of white matter damage. Mechanistically, Erk5 exacerbates white matter damage by promoting microglial ferroptosis through the phosphorylation of nuclear factor of activated T-cells, cytoplasmic 4 (Nfatc4), which subsequently activates the expression of cleft lip and palate transmembrane protein 1-like protein (Clptm1l), a lipid scramblase involved in ferroptosis. Pharmacological and genetic inhibition of Erk5 in microglia effectively mitigates oxidative stress, lipid peroxidation, and ferroptosis, leading to a reduction in white matter damage and improved cognitive function. These findings underscore the potential of targeting the Erk5-Nfatc4-Clptm1l axis as a therapeutic strategy for ischemic white matter damage. Our study offers valuable insights into the molecular pathways driving white matter damage and provides a framework for the clinical translation of Erk5 inhibitors in the treatment of ischemic white matter damage.