N-acetylated amino acids: an overlooked layer of metabolic regulation

N-acetylated amino acids (Ac-AAs) have been repeatedly reported in metabolomics studies of high-intensity exercise, cold-exposed brown adipose tissue (BAT), and various pathological conditions. Despite their recurrent detection, the origins and physiological functions of Ac-AAs remain poorly understood, and evidence is fragmented across diverse scientific disciplines. While Ac-AAs have traditionally been attributed to the degradation of N-terminally acetylated proteins, this mechanism alone cannot fully account for their diversity and context-dependent regulation. Instead, accumulating evidence supports a model in which Ac-AA formation is driven by elevated intracellular acetyl-CoA and amino acid availability. Under these conditions, Ac-AA formation may represent a previously unrecognized metabolic mechanism involved in acetyl-CoA and amino acid homeostasis. In this review, we provide an overview of Ac-AA alterations across physiological contexts, synthesize current evidence on their origins, regulation, and physiological functions, and propose a mechanistic framework for the role of Ac-AAs in metabolic regulation. By integrating findings across diverse scientific disciplines, this review establishes a foundation for a more consistent interpretation of Ac-AAs across physiological and pathological contexts.