SUMMARY Heart failure is a leading cause of death worldwide, and the leading cause of hospital admissions in patients over 65 in the US. The role of metabolism in cardiac pathology has long been of interest, but no therapies that target cardiac metabolism are known. Recently, Na+/glucose transporter 2 inhibitors (SGLT2i), originally designed as therapies for diabetes, have taken HF management by storm, demonstrating 20-30% reductions in heart failure hospitalizations in large phase III trials, even in patients without diabetes. How SGLT2i confer these benefits remains a mystery. In extensive preliminary data, we now show that SGLT2i directly activate pantothenate kinase (PANK), the first and rate-limiting enzymatic step in the synthesis of co-enzyme A (CoA) from pantothenate (vitamin B5). CoA is an obligate intracellular metabolite critical for most oxidative processes, especially in highly oxidative tissues like the heart. We show in our preliminary data SGLT2i directly promote cardiac CoA synthesis and oxidative metabolism, and promote cardiomyocyte contractility. Together our data lead us to hypothesize that: SGLT2i confer benefit in heart failure by activating PANK and boosting cardiac CoA metabolism. We will test this hypothesis in depth by: Aim 1: Understand the consequences of SGLT2i on cardiac CoA metabolism and fuel use. Aim 2: Test in vivo the role of cardiac PANK in the heart failure protection conferred by SGLT2i. Aim 3: Identify the molecular mechanism of activation of PANK by SGLT2i. Aim 4: Begin a discovery campaign of novel small molecules to target PANK but not SGLT2. These highly focused studies will elucidate how SGLT2i target PANK, and in turn protect from heart failure. Precise structural and physiological understanding of how SGLT2i target PANK will enable design of small molecules that improve on SGLT2i efficacy and reduce the side effects of SGLT2i. Success in these studies will thus potentially open the door for the generation of entirely ne