We previously reported that TRIM15 dysregulated lipid metabolism to promote pancreatic cancer progression.[10] We also found that TRIM15 activated the AKT signaling pathway to decrease the sensitivity of liver cancer cells to tyrosine kinase inhibitors.[11] Meanwhile, TRIM15 is considered an inflammation‐related protein regulated by TNF‐α, and it inhibits TLR4.[12, 13] In this study, we demonstrated that TRIM15 is a key molecule in the obesity‐induced progression of EAC by degrading YY2, which in turn inhibits FOXRED1 transcription to regulate lipid and energy metabolism. Here, TLR4 is linked to Obesity.