Abstract

Chronic inflammation promotes esophageal cancer (EC) progression through NFκB activation, yet the downstream effector genes driving EC progression remain incompletely characterized. Here, we identify syndecan-4 (SDC4) as a new NFκB target gene that is upregulated in EC and associated with poor prognosis. The pro-inflammatory cytokine IL1β stimulates EC cell proliferation and concurrently induces SDC4 expression in an NFκB-dependent manner. Mechanistically, NFκB directly binds to the SDC4 promoter region, which is enriched with the active chromatin marker H3K27Ac. Functional studies demonstrate that SDC4 is necessary for IL1β-driven proliferation, as its knockdown suppresses, whereas overexpression enhances EC cell proliferation. Notably, the natural compound epigallocatechin gallate (EGCG) effectively blocks this IL1β-NFκB-SDC4 axis by inhibiting NFκB nuclear translocation, thereby attenuating SDC4 upregulation and subsequent EC cell proliferation. Our findings establish SDC4 as a critical molecular link between inflammation and EC progression, and highlight EGCG as a potential therapeutic candidate targeting this pathway.