Protein acylation and bone metabolism: bidirectional crosstalk linking metabolic reprogramming to skeletal homeostasis.

Protein acylation is an important class of post-translational modifications that uses acyl-coenzyme A (acyl-CoA) metabolites as donor substrates. Regulated by writers, erasers, and readers, these modifications dynamically control protein activity, stability, localization, and signaling, thereby linking cellular metabolism to functional adaptation. Bone homeostasis depends on the balance between osteoblast-mediated bone formation and osteoclast-driven bone resorption. Emerging evidence indicates that protein acylation is not only a regulator of skeletal remodeling, but also a metabolic sensor shaped by bone-cell reprogramming. In this review, we summarize the metabolic origins, regulatory enzymes, and skeletal functions of major acylation modifications, including acetylation, succinylation, lactylation, and palmitoylation. These modifications influence osteoblast differentiation, osteoclastogenesis, mitochondrial homeostasis, and microenvironmental adaptation through key targets such as Runx2, Osterix, p53, and superoxide dismutase 2 (SOD2). Conversely, metabolic transitions in bone cells, including enhanced glycolysis, mitochondrial activation, fatty acid oxidation, and tricarboxylic acid (TCA) cycle remodeling, reshape intracellular acyl-CoA availability and thereby alter cellular acylation patterns. This bidirectional crosstalk forms a dynamic metabolism-acylation-function axis whose dysregulation may contribute to osteoporosis, osteoarthritis, and other skeletal disorders. Understanding this regulatory network may provide candidate biomarkers and therapeutic targets for precision management of metabolic bone diseases.