EPO Deficiency Upregulates GADD45b/p38 MAPK Axis, Mediating Schizophrenia‐Related Synaptic and Cognitive Impairments

Abstract Schizophrenia (SZ) is a chronic and severe mental illness associated with psychiatric symptoms, cognitive deficits, and social dysfunction. Current clinical interventions only limit relief of psychiatric symptoms and have minimal impact on cognitive impairments. Erythropoietin (EPO), known for its role in neurogenesis and synaptic plasticity, is significantly low in SZ patients. However, the role of EPO deficiency in SZ‐associated cognitive deficits remains unclear. In this study, we used the MK801‐induced SZ rat model to show that EPO levels were significantly decreased, correlating with cognitive impairments. EPO supplementation mitigated apoptosis, synaptic damage, and cognitive impairments caused by MK801. RNA‐sequencing and Western blot analysis revealed increased expression of growth arrest and DNA damage 45b (GADD45b) in MK801‐treated rats, reversed by EPO supplementation. Moreover, overexpression of GADD45b exacerbated neuronal loss and cognitive impairments in male Sprague‐Dawley rats, while downregulation of GADD45b rescued these SZ‐related pathologies. Notably, the benefits of EPO supplementation on SZ pathology were blocked by GADD45b overexpression. Inhibition of p38 MAPK, a GADD45b target, reduced MK801‐induced apoptosis and synaptic damage. These findings uncover a novel etiopathogenic mechanism of SZ‐related cognitive impairments, driven by EPO deficiency and the activation of the GADD45b/p38 MAPK axis.