Abstract: OBJECTIVE To explore the effect and mechanism of a novel polycyclic spiro-epoxy indole compound on suppression of lung cell lines proliferation. METHODS The compound’s effect on cellular proliferation, apoptosis, and cellular migration was determined using the MTT assays, flow cytometry, and cell scratch test. The target proteins of this compound were then predicted using the PharmMapper platform, while the associated proteins in lung adenocarcinoma were predicted using the GEPIA platform. In order to determine the effect of this compound on the target gene at the promoter level, transcription level, and expression level, reporter gene assay, qPCR assay and Western blotting test were also performed. RESULTS The results showed that this compound inhibited the proliferation of SKLU1 cell line with an IC₅₀ value of 11.38 μmol·L^-1, inhibited the cell migration of SKLU1 above the concentration of 2.85 μmol·L^-1, and induced the apoptosis above the concentration of 5.69 μmol·L^-1. Additionally, this compound might target the RhoGEF7 and inhibit the cellular migration by down-regulating the expression of Rac1 protein and E-cadherin protein. Then the down-regulated Rac1 protein suppressed the activation of NF-κB, which reduced the transcription of downstream genes IL-6 and IL-8. Moreover, the IL-6/JAK/STAT3 pathway was inhibited when Rac1 protein was down-regulated. CONCLUSION This study provides theoretical basis for the molecular mechanism of targeting lung cancer cells with this novel polycyclic spiro epoxidized indole compound.