In multiple sclerosis (MS), oligodendrocyte (OL) degeneration and subsequent demyelination in the central nervous system (CNS) causes neurological impairment. Monocarboxylate transporter 8 (MCT8) may promote OL maturation and myelination by actively transporting thyroid hormone (TH) into the CNS and thereby facilitating key transcription and metabolomic pathways for myelin biogenesis. Diiodothyropropionic acid (DITPA), a synthetic TH-analog, can be transported into the CNS, independent of MCT8 and may promote OL maturation and myelination. In this study, we investigated the potential of DITPA to limit OL dystrophy and promote remyelination in the context of neuroinflammation, to demonstrate potential therapeutic efficacy for neuro-protection/repair during MS.Using archival human tissue, white matter demyelinated lesions from individuals with secondary progressive MS (SPMS) displayed significantly reduced MCT8 expression levels along with intracellular deiodinase 2 and 3, illustrating a brain hypothyroid state which may drive progressive disease. Furthermore, the metabolomic analysis indicated dysregulated TH signaling due to MCT8-deficiency and abrogated downstream AKT-mTOR-PANK2 signaling pathways.Utilising OLs derived from the NKX2.1-GFP human embryonic stem cell (hESC) reporter line, in-vitro treatment with DITPA outperformed active Triiodothyronine (T3), and MCT8-independent TH-analog, triiodothyroacetic acid (TRIAC), by enhancing OL differentiation and myelination of cocultured retinal ganglion cells during MCT8-knockdown.Preclinical studies in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS demonstrated that DITPA promoted the AKT-mTOR-PAK2 signaling pathway and enhanced neuroprotection and remyelination, when benchmarked against other synthetic TH analogs, TRIAC and LT3.Collectively, these data emphasise that DITPA may signal neuroprotection and has potential as a therapeutic intervention for MS.