Abstract Body: Introduction and hypothesis: Myocardial infarction induces cardiomyocyte death and adverse remodeling that contributes to progression to heart failure despite current therapies. TAOK1, a stress responsive serine threonine kinase, was identified as a regulator of doxorubicin induced cardiomyocyte death using a pooled CRISPR screen in human pluripotent stem cell derived cardiomyocytes, and its inhibition attenuated doxorubicin induced cardiomyopathy in mice. We hypothesized that TAOK1 inhibition would limit ischemia induced injury and attenuate post infarction remodeling. Methods and Results: Male C57BL/6J mice received AAV9 mediated cardiac delivery of shRNA targeting Taok1 or control vector prior to permanent ligation of the left anterior descending artery. Cardiac function and remodeling were evaluated 21 days after myocardial infarction. In parallel, human induced pluripotent stem cell derived cardiomyocytes were subjected to TAOK1 knockdown and exposed to hypoxia or endothelin-1. At 21 days after myocardial infarction, survival was significantly higher in sh-Taok1 mice (90.9%) compared with sh-scramble mice (50.0%, p = 0.03). Left ventricular ejection fraction was preserved in sh-Taok1 mice (52.5 ± 1.7%) relative to sh-scramble mice (43.0 ± 3.6%, p = 0.02). Histological analyses demonstrated reduced TUNEL positive nuclei in the ischemic border zone (0.30% vs 0.79%, p = 0.01) and decreased fibrosis (10.0% vs 16.0%, p = 0.02) in sh-Taok1 hearts. In human cardiomyocytes, TAOK1 knockdown reduced hypoxia induced cell death (4.6% vs 7.3%, p < 0.01) and cleaved caspase-3 expression. TAOK1 suppression also attenuated endothelin-1 induced hypertrophy, reflected by reduced cell size (25.6% reduction, p = 0.04) and lower expression of NPPA (p < 0.01) and NPPB (p < 0.01). Mechanistically, TAOK1 inhibition attenuated p38 activation under hypoxia and reduced JNK activation during endothelin-1 stimulation, consistent with suppression of stress activated kinase signaling. Conclusion: TAOK1 inhibition improves survival and attenuates adverse remodeling after myocardial infarction. Targeting TAOK1 suppresses stress activated kinase signaling and protects cardiomyocytes from ischemic and hypertrophic injury, suggesting that TAOK1 may be a potential therapeutic target.