SIRT2 functions as an N-acetylaspartate hydrolase that counteracts cardiac metabolic remodeling in kidney disease

N-acetylated amino acids systemically accumulate in the circulatory system in patients with chronic kidney disease (CKD), raising questions about their roles in peripheral tissues1,2. Here, targeted metabolomics in patients with CKD identified that circulating N-acetylaspartate (NAA) as the metabolite most closely linked to early cardiac dysfunction. In mice, both CKD and exogenous NAA administration induced pronounced cardiac NAA accumulation, resulting in systolic dysfunction and pathological hypertrophy. Activity-based protein profiling identified cytosolic malate dehydrogenase 1 (MDH1) and sirtuin 2 (SIRT2) as direct targets of NAA. NAA acts as a substrate analogue that occupies the MDH1 substrate-binding pocket, competitively inhibits its enzymatic activity, and disrupts the malate–aspartate shuttle, thereby lowering cytosolic and mitochondrial NAD⁺/NADH ratios, suppressing tricarboxylic acid cycle flux, and compromising cardiomyocyte energy metabolism. Notably, we identified SIRT2 as a previously unrecognized NAA hydrolase that specifically binds and hydrolyzes NAA in an NAD⁺-dependent manner, thereby mitigating NAA-induced metabolic stress. Cardiomyocyte-specific restoration of SIRT2 activity in mice reduced cardiac NAA levels, improved systolic dysfunction, and attenuated hypertrophy. These findings expand sirtuins from protein deacylases to direct regulators of small-molecule metabolites and establish NAA as a kidney–heart metabolic mediator, revealing an amino acid acetylation-dependent layer of energy homeostasis.