Mast cells (MCs) are sentinels of the innate immune system, poised to rapidly respond to exogenous stress and to endogenous danger signals. However, the role of MCs in IDD is still unclear. We used single cell RNA sequencing (scRNA-seq) mapped the profile of MCs in human nucleus pulposus (NP) tissues and revealed interaction between MCs and disc cells for the first time. A wide variety of stimuli can influence MCs degranulation and release of pre-formed mediators including tryptases, chymase pro-inflammatory lipids, cytokines and chemokines. Cigarette smoking (CS) is a typical stimuli for MCs activation and degranulation. Our CS exposure model showed 8 weeks and 12 weeks CS exposure induced MCs significantly increased and aberrantly activated in disc tissues. Next, we performed proteomic and histology to demonstrate inflammation and matrix destruction in discs of CS exposure mouse. We used immunol fluorescence and transcriptomic analyses showed tryptases, instead of chymase, are elevated in human degenerated NP tissues. Notably, the differences are dramastical in smokers compared with non-smokers. Lastly, we co-cultured human bone marrow derived MCs (BMMCs) and human NP cells, and demonstrated BMMCs from smokers can impact DNA methylation and degeneration of human NP cells. Our findings demonstrated the role of MCs in the pathogenesis of IDD. Smoking can contribute to MCs function of this process, making IDD in smokers might to be a specific pathology type.