BACKGROUND Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2a) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2a phosphorylation is observed in mouse and human atheroma. OBJECTIVES Potent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated the potential benefits of intercepting ISR in a chronic metabolic and inflammatory disease, atherosclerosis. METHODS The authors investigated ISR's role in lipid-induced inflammasome activation and atherogenesis by taking advantage of 3 different small molecules and the ATP-analog sensitive kinase allele technology to intercept ISR at multiple molecular nodes. RESULTS The results show lipid-activated eIF2a signaling induces a mitochondrial protease, Lon protease 1 (LONP1), that degrades phosphatase and tensin-induced putative kinase 1 and blocks Parkin-mediated mitophagy, resulting in greater mitochondrial oxidative stress, inflammasome activation, and interleukin-1b secretion in macrophages. Furthermore, ISR inhibitors suppress hyperlipidemia-induced inflammasome activation and inflammation, and reduce atherosclerosis. CONCLUSIONS These results reveal endoplasmic reticulum controls mitochondrial clearance by activating eIF2aLONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1b secretion by dietary fats. These findings underscore the intricate exchange of information and coordination of both organelles' responses to lipids is important for metabolic health. Modulation of ISR to alleviate organelle stress can prevent inflammasome activation by dietary fats and may be a strategy to reduce lipid-induced inflammation and atherosclerosis. (J Am Coll Cardiol 2019; 73: 1149-69) (c) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).