In this study transcriptome and lipidome profiling of triple negative breast cancer cells subjected to pharmacological inhibition of IRE1α revealed changes in lipid metabolism genes associated with an accumulation of triacylglycerols (TAGs). We identified DGAT2 mRNA, encoding the rate-limiting enzyme in TAG biosynthesis, as a RIDD target. Mechanistically, the DGAT2 transcript is cleaved by IRE1 at guanine 260 within a hairpin stem loop structure. Our results highlight the importance of IRE1 RIDD activity in reprograming cellular lipid metabolism Overall design: Triple negative breast cancer MDA-MB-231 cells were treated with 20 μM MKC8866 or DMSO for 8 and 24 h after which RNA was extracted and transcriptomic profile determined with RNA sequencing (n=3).