Gain-of-function PPM1D mutations attenuate ischemic stroke

Patients carrying PPM1D mutations exhibit better stroke-related clinical phenotypes, including improvements in systolic blood pressure, fibrinogen level, low-density lipoprotein, and plateletcrit level. Experimental brain ischemia in Ppm1d-deficient (Ppm1d-/-) mice resulted in enlarged lesions and pronounced neurological impairments. Spatial transcriptomics revealed a distinct Ppm1d-associated gene expression pattern, indicating disrupted endothelial homeostasis during ischemic brain injury. Proteomic analysis demonstrated that differentially expressed proteins in primary brain endothelial cells from Ppm1d-/- mice were significantly enriched in the peroxisome proliferator-activated receptors (PPARs)-mediated metabolic signaling. Mechanistically, Ppm1d deficiency promoted aberrant fatty acid β-oxidation and increased oxidative stress, which impair endothelial cell function through the PPARα pathway. A small molecule, T2755, was identified to engage Trp427 and stabilize PPM1D protein, thereby mitigating ischemic brain injury in mice. Collectively, we found that PPM1D protects against ischemic brain injury and validates its pharmacological stabilizer T2755 as a promising therapy for ischemic stroke.