Plumbagin ameliorates multiple sclerosis by inducing DDX3X-mediated stress granule assembly in mice.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with limited therapeutic options. Stress granules (SGs), membraneless organelles formed via liquid-liquid phase separation (LLPS) in response to cellular stress, function as a cytoprotective mechanism against stress induced apoptosis and pyroptosis. SGs can counteract NLRP3 inflammasome by sequestering dead-box helicase 3 X-linked (DDX3X), thereby promoting the survival of pyroptotic cells. Here, we identified that plumbagin (PL), a natural naphthoquinone with antioxidant and anti-inflammatory properties, as a novel SG inducer. In microglia, PL induced SGs that suppressed NLRP3-mediated pyroptosis and subsequent mitochondrial dysfunction, with DDX3X as a potential target. Furthermore, PL alleviated neuroinflammation and demyelination and suppressed oxidative stress in the CNS of both the cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) mouse models. Our findings reveal that PL can mitigate neuroinflammation and myelin damage by modulating the DDX3X-SG axis, supporting a novel therapeutic strategy for MS.