# Obesity‐Associated TRIM15 Promotes the Proliferation of Esophageal Adenocarcinoma Through the YY2/FOXRED1 Axis

## TL;DR

Obesity-related TRIM15 protein promotes the growth of esophageal cancer by disrupting lipid metabolism and making cancer cells resistant to a type of cell death called ferroptosis.

## Contribution

The study identifies a new TRIM15/YY2/FOXRED1 pathway linking obesity to esophageal adenocarcinoma progression.

## Key findings

- TRIM15 promotes EAC cell proliferation by degrading YY2 via the ubiquitin-proteasome system.
- YY2 suppression leads to reduced FOXRED1 expression, dysregulating lipid and energy metabolism in EAC cells.
- The TRIM15/YY2/FOXRED1 axis modulates ferroptosis sensitivity through mTOR/c-MYC and GPX4 pathways.

## Abstract

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.

The study identifies TRIM15 as a key driver in the development of obesity‐associated esophageal adenocarcinoma (EAC). Mechanistically, TRIM15 degrades YY2 through the proteasome pathway, suppressing FOXRED1 transcription and ultimately accelerating tumor proliferation. We further characterize the critical role of the TRIM15/YY2/FOXRED1 axis in the dysregulation of lipid metabolism and ferroptosis in EAC.