Carabrone alleviates neuroinflammation by covalently targeting ubiquitin conjugating enzyme UBE2D3 in experimental...

Multiple sclerosis (MS) is an incurable and progressive inflammatory disease of the central nervous system (CNS) characterized by inflammatory demyelination, chronic axonal damage, and neurodegeneration. Carabrone (CA), a sesquiterpene lactone from the traditional Chinese herb Carpesium abrotanoides L., demonstrates diverse pharmacological properties. However, its therapeutic effects on MS and the underlying mechanisms remain unexplored. In the present study, we reported the beneficial effects of CA on experimental autoimmune encephalomyelitis (EAE), a well-established mouse model of MS, for the first time. Treatment with CA markedly attenuated disease progression induced by myelin oligodendrocyte glycoprotein (MOG_35-55) peptide, as evidenced by reduced clinical severity, diminished inflammatory cell infiltration into the CNS, and a decrease in demyelinated lesions. Mechanistically, CA could covalently bind to the cysteine 85 (Cys85) residue of ubiquitin conjugating enzyme E2 D3 (UBE2D3), thereby inhibiting the phosphorylation of inhibitor of nuclear factor-kappa B alpha (IκBα) and its subsequent ubiquitin-mediated degradation, ultimately leading to suppression of the nuclear factor-κB (NF-κB) signaling pathway. These findings were further confirmed in macrophages via siRNA-mediated knockdown of UBE2D3. Taken together, our results revealed that CA is a novel UBE2D3 inhibitor and provided a promising therapeutic candidate for MS.