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Understanding the mechanism by which sulforaphene (SFE) affects esophageal squamous cell carcinoma (ESCC) contributes to the application of this isothiocyanate as a chemotherapeutic agent. Thus, we attempted to investigate SFE regulation of ESCC characteristics more deeply. We performed gene set enrichment analysis (GSEA) on microarray data of SFE-treated ESCC cells and found that differentially expressed genes are enriched in TNFα_Signaling_via_the_NFκB_Pathway. Coupled with the expression profile data from the GSE20347 and GSE75241 datasets, we narrowed the set to 8 genes, 4 of which (C-X-C motif chemokine ligand 10 (<i>CXCL10</i>), TNF alpha induced protein 3 (<i>TNFAIP3</i>), inhibin subunit beta A (<i>INHBA</i>), and plasminogen activator, urokinase (<i>PLAU</i>)) were verified as the targets of SFE. RNA-sequence (RNA-seq) data of 182 ESCC samples from The Cancer Genome Atlas (TCGA) were grouped into two phenotypes for GSEA according to the expression of <i>CXCL10</i>, <i>TNFAIP3</i>, <i>INHBA</i>, and <i>PLAU</i>. The enrichment results proved that they were all involved in the NFκB pathway. ChIP-seq analyses obtained from the Cistrome database indicated that NFκB-p65 is likely to control the transcription of <i>CXCL10</i>, <i>TNFAIP3</i>, <i>INHBA</i>, and <i>PLAU</i>, and considering <i>TNFAIP3</i> and <i>PLAU</i> are the most significantly differentially expressed genes, we used chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR) to verify the regulation of p65 on their expression. The results demonstrated that SFE suppresses ESCC progression by down-regulating <i>TNFAIP3</i> and <i>PLAU</i> expression in a p65-dependent manner.