Beyond acetylation: Evaluating the emerging biology of lysine acylation

Lysine acylation has emerged as a rapidly expanding family of post-translational modifications that directly links cellular metabolism to protein regulation. Beyond lysine acetylation, advances in mass spectrometry and chemical biology have uncovered a diverse repertoire of acyl modifications spanning short-chain, branched, unsaturated, aromatic, and dicarboxylic groups. Together these modifications establish lysine acylation as a molecular interface through which metabolic state can shape protein function, chromatin regulation, and cell signaling. Yet fundamental questions remain regarding their biological significance, enzymatic regulation, site specificity, and whether many acylations function as bona fide regulatory signals or reflect metabolite-driven mechanisms. Here, we synthesize the current understanding of the metabolic origins, structural and biochemical properties, and their writer, reader, and eraser systems that govern lysine acylations. We further highlight emerging chemical biology approaches for detecting, manipulating, and functionally interrogating acyl marks and discuss the conceptual and technological advances needed to distinguish closely related modifications and establish their causal biological roles.