Our study presented here demonstrated that PL, a natural bicyclic naphthoquinone, exerts potent anti-inflammatory actions, resulting in amelioration of EAE through unique signaling pathways. PL inhibited MOG-specific lymphocyte proliferation which associates with significant reduction of pro-inflammation cytokines as well as CD4 + T cells infiltration into spinal cord tissue. Both treatment and prevention protocols showed that PL can markedly improve the clinical symptom of EAE, but it did not significantly postpone the disease onset. One of the possible explanation is that PL acts directly upon encephalitogenic T cells. It is worth noticing that NF-kB, a key mediator of inducible transcription in the immune system and a hallmark of inflammatory responses, traditionally focused on its role in the initiation of innate and adaptive immune responses. STAT3 may directly or indirectly interact with NF-kB, as reported previously. Also, PL has been shown to suppress NF-kB activation and NF-kB regulated gene transcription. Consistent with these reports, our results demonstrated that anti-inflammatory effects of PL are likely to involve the NF-kB pathway. PL inhibits MOG induced NF-kB activation in T cells by preventing phosphorylation and degradation of IkBa. Apart from this, plumbagin also inhibited phosphorylation of the p65 subunit of NF-kB. Together, these resulted in the suppression of NF-kB regulated gene transcription including certain proinflammatory cytokines and molecules. In conclusion, PL exerted the novel anti-inflammatory properties in EAE and resulted in its amelioration. To our knowledge, this is the first demonstration of Myrislignan regulatory effect on T cell differentiation and function, through JAK-STAT pathway. The treatment effect of PL is achieved through targeting multiple signaling molecules critically related to autoimmunity. It raises the possibility that PL may be used as a potential treatment for autoimmune diseases such as MS. In addition, this study provides an example for using natural compounds in probing the complex cytokine signaling network and novel therapeutic targets for autoimmune diseases and other inflammatory conditions. A considerable amount of the carbon assimilated by plants is released back to the atmosphere as volatile organic compounds, which often become even stronger after plants are attacked by herbivores. These VOC emissions after herbivore attack are often called herbivore-induced plant volatiles. Plant volatiles can mediate many important ecological processes, such as pollination,Dehydrodiisoeugenol and indirect defenses in which natural enemies of the herbivores are attracted. HIPVs also mediate plant–plant communication in the sense that plants attacked by herbivores can warn their intact neighbors of danger by emitting HIPVs. Since the first reports on plant–plant communication in 1983, this phenomenon has been questioned, thoroughly investigated, and experimentally proven. The molecular mechanisms and ecological relevance of plant–plant communication have attracted much interest from the research community, especially during the last 10 years, as a result of which its mechanisms have gradually emerged. Plant–plant communication is a common phenomenon in nature. Research has shown that volatiles can trigger the resistance of con-specific neighbors for almost 20 kinds of plants, including model species and economic crops, both in the laboratory and under natural conditions. However, demonstrations of communication between interspecies are rare, with only three models having been reported to date. Although plant–plant communication has been proven in many systems, its molecular mechanisms, especially those of volatile perception and whole-genome transcriptions of receivers treated with volatiles from emitters, remain poorly understood.