Tumor-associated lymphangiogenesis has attracted increasing attention because of its potential contribution to lymph node metastasis. However, the molecular mechanisms underlying lymphangiogenesis in cancer remains elusive. In the current study, we demonstrate that tripartite motif-containing 3 (TRIM3) directly interacts with and induces E3 ligase-dependent proteasomal turnover of importin α3 and α-Actinin-4 (ACTN4), which controls nuclear factor kappa B (NF-κB) activity at a well-ordered level. Heterozygous deletion-mediated TRIM3 downregulation led to NF-κB constitutive activation through disruption of the NF-κB-IκB-α negative feedback loop and enhancement of the p65 DNA-binding affinity and transcriptional activity via promoting symmetrical dimethylarginine modification of NF-κB/p65 at Arg30 and Arg35, which consequently promoted lymphatic metastasis of esophageal squamous cell carcinoma (ESCC) cells. Treatment with Tecfidera, a medication used to treat multiple sclerosis, restored the negative feedback inhibition of NF-κB by reducing the NF-κB/ACTN4 interaction and decreasing symmetrically dimethylated NF-κB levels, resulting in inhibition of ESCC lymphatic metastasis both in vitro and in vivo. Taken together, our results uncover a novel mechanism for constitutive NF-κB activation in cancer and may represent an attractive strategy to treat ESCC lymphatic metastasis.