Multiple sclerosis (MS) is a progressive and inflammatory demyelinating disease of the CNS. Peroxisomes perform critical functions that contribute to CNS homeostasis. We investigated peroxisome injury and mitigating effects of peroxisome-restorative therapy on inflammatory demyelination in models of MS. Human autopsied CNS tissues (male and female), human cell cultures, and cuprizone-mediated demyelination mice (female) were examined by RT-PCR, Western blotting, and immunolabeling. The therapeutic peroxisome proliferator, 4-phenylbutyrate (4-PBA) was investigated in vitro and in vivo . White matter from MS patients showed reduced peroxisomal transcript and protein levels, including PMP70, compared with non-MS controls. Cultured human neural cells revealed that human microglia contained abundant peroxisomal proteins. TNF-α-exposed microglia displayed reduced immunolabeling of peroxisomal proteins, PMP70 and PEX11β, which was prevented with 4-PBA. In human myeloid cells exposed to TNF-α or nigericin, suppres...