Obesity has been identified as an independent risk factor for gastroesophageal reflux disease (GERD) and esophageal adenocarcinoma (EAC). Oxidative stress and inflammation driven by chronic GERD are the main causes of the tumorigenesis of EAC, but the underlying mechanism remains elusive. Here, the inflammation-upregulated E3 ligase, tripartite motif 15 (TRIM15), is identified as a key driver of obesity-associated EAC. TRIM15 promotes the degradation of YY2 is demonstrated through the ubiquitin-proteasome system, which in turn dysregulates lipid metabolism and enhances the proliferation of EAC cells. Furthermore, YY2 transcriptionally is shown that increases FOXRED1 expression. FOXRED1 is subsequently identified as an essential effector for the TRIM15-induced dysregulation of lipid and energy metabolism in EAC cells. Thus, a novel obesity-associated TRIM15/YY2/FOXRED1 axis is identified that contributes to the proliferation of EAC. Given that lipid metabolism regulates ferroptosis by controlling cellular processes associated with phospholipid peroxidation. The TRIM15/YY2/FOXRED1 axis demonstrates that it modulates SLC3A2 expression via the mTOR/c-MYC pathway, thereby regulating GPX4 levels to influence EAC sensitivity to ferroptosis-inducing compounds and proposing a therapeutic strategy for EAC.