Cytochrome P450-mediated vitamin D and cholesterol metabolism in the pathophysiology of neurodevelopmental disorders.

Cytochrome P450 (CYP450) enzymes play critical roles in the pathophysiology of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), Rett syndrome (RTT), and attention-deficit hyperactivity disorder (ADHD). Although traditionally associated with hepatic and intestinal xenobiotic metabolism, several CYP450 isoforms are expressed in the central nervous system, where they regulate essential pathways involving vitamin D and cholesterol-two molecules fundamental to neural development, synaptogenesis, and membrane homeostasis. The cholesterol-CYP27A1-27-hydroxycholesterol (27-OHC)-liver X receptor (LXR) axis has emerged as a critical regulator of neurodevelopment, influencing INSIG proteins, LXRs, and LDL receptors. Additionally, members of the CYP1A, CYP2B, CYP2C, and CYP3A families contribute to neuroendocrine balance and fetal brain maturation. Dysregulation of these pathways may contribute to synaptic dysfunction, neuronal hyperexcitability, and metabolic imbalance observed in NDDs. This review highlights the interplay between CYP450 enzymes, vitamin D metabolism, and cholesterol homeostasis, emphasizing their mechanistic relevance in ASD and related disorders, and discusses the therapeutic potential of targeting CYP450-mediated pathways to restore metabolic and neurodevelopmental equilibrium.