This study investigates the regulated Ire1-dependent decay (RIDD) of messenger RNAs (mRNAs) in mammalian cells. Ire1, a transmembrane protein, is activated by ER stress and has a cytoplasmic nuclease domain that cleaves mRNAs, enabling splicing and activation of XBP-1, a key transcription factor in the unfolded protein response (UPR). The study shows that in mouse fibroblasts, Ire1-dependent degradation of mRNAs occurs in response to ER stress, and this process requires Ire1's nuclease activity, not its kinase activity. RIDD is a conserved pathway in mammalian cells, distinct from XBP-1 splicing, and involves the degradation of mRNAs encoding membrane and secreted proteins. The nuclease activity of Ire1 is essential for RIDD, and the pathway is regulated by ER stress. The study also demonstrates that RIDD can be induced by a small molecule that activates Ire1's nuclease activity without requiring ER stress. The results suggest that RIDD is a distinct mechanism that helps relieve the ER's folding burden and may have implications for cellular stress responses, including viral infections and diseases like multiple myeloma. The findings highlight the complexity of Ire1's functions in the UPR and its potential role in various physiological and pathological conditions.This study investigates the regulated Ire1-dependent decay (RIDD) of messenger RNAs (mRNAs) in mammalian cells. Ire1, a transmembrane protein, is activated by ER stress and has a cytoplasmic nuclease domain that cleaves mRNAs, enabling splicing and activation of XBP-1, a key transcription factor in the unfolded protein response (UPR). The study shows that in mouse fibroblasts, Ire1-dependent degradation of mRNAs occurs in response to ER stress, and this process requires Ire1's nuclease activity, not its kinase activity. RIDD is a conserved pathway in mammalian cells, distinct from XBP-1 splicing, and involves the degradation of mRNAs encoding membrane and secreted proteins. The nuclease activity of Ire1 is essential for RIDD, and the pathway is regulated by ER stress. The study also demonstrates that RIDD can be induced by a small molecule that activates Ire1's nuclease activity without requiring ER stress. The results suggest that RIDD is a distinct mechanism that helps relieve the ER's folding burden and may have implications for cellular stress responses, including viral infections and diseases like multiple myeloma. The findings highlight the complexity of Ire1's functions in the UPR and its potential role in various physiological and pathological conditions.