CYP46A1 ‐Targeted Treatment Alleviates Long‐Term White Matter Injury Following Traumatic Brain Injury by Promoting Cholesterol Metabolic Clearance and Remyelination

AIM: Cholesterol plays a critical role in repairing white matter injury (WMI) following traumatic brain injury (TBI). The enzyme cholesterol 24-hydroxylase (CYP46A1) regulates the removal of cholesterol by converting it into 24(S)-hydroxycholesterol (24OHC). Although CYP46A1 has neuroprotective effects on various central nervous system disorders, its effect on WMI remains unclear. METHODS: mice were utilized to elucidate the function of CYP46A1. Neurological function, WMI, and cholesterol metabolism were evaluated, and the mechanisms through which CYP46A1 affects these processes were explored. RESULTS: Efavirenz markedly improved outcomes and preserved white matter structure after TBI by increasing microglial phagocytic activity and myelin debris clearance, along with promoting oligodendrocyte precursor cell remyelination. Furthermore, efavirenz promoted cholesterol export by increasing 24OHC levels and activating liver X receptors (LXR). However, these neuroprotective effects of Efavirenz were partially diminished when CYP46A1 was knocked down or when LXR activity was blocked. CONCLUSION: Efavirenz administration promotes functional neurological recovery and sustains white matter integrity in TBI through the regulation of cholesterol homeostasis and the promotion of remyelination processes.