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 familial pancreatic carcinoma.