Obesity-associated TRIM15 promotes the proliferation of esophageal adenocarcinoma through the YY2/FOXRED1 axis

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, we identified the inflammation-upregulated E3 ligase, tripartite motif 15 (TRIM15) as a key driver of obesity-associated EAC. We demonstrated that TRIM15 promotes the degradation of YY2 through the ubiquitin-proteasome system, which in turn dysregulates the lipid metabolism and enhances the proliferation of EAC cells. Furthermore, we showed that YY2 transcriptionally increases FOXRED1 expression. We then found that FOXRED1 is one of the essential effectors for the TRIM15-induced dysregulation of lipid and energy metabolism in EAC cells. Thus, we identified a novel obesity-associated TRIM15/YY2/FOXRED1 axis that contributes to the proliferation of EAC. Given that lipid metabolism regulates ferroptosis by controlling cellular processes associated with phospholipid peroxidation. We show that the TRIM15/YY2/FOXRED1 axis regulates EAC sensitivity to ferroptosis-inducing compounds by modulating the levels of SLC3A2 and GPX4, providing a therapeutic strategy for EAC.