The emerging role of NAT10-mediated N4-acetylcytidine modification of RNA in bone diseases: Current frontiers and future challenges.
AIMS To review the biosynthesis, regulatory mechanisms, and functional roles of N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) RNA modification in bone and joint diseases, and to evaluate its therapeutic potential. MATERIALS AND METHODS A systematic literature search was conducted using PubMed, Web of Science, and Scopus databases for articles published up to May 2026 addressing NAT10, ac4C RNA modification, and bone diseases including osteoporosis, inflammatory bone loss, osteoarthritis, osteosarcoma, and bone marrow mesenchymal stem cell (BMSC) differentiation. Studies investigating ac4C modification mechanisms, detection methods, and therapeutic interventions were critically reviewed and synthesized. KEY FINDINGS NAT10, the primary known ac4C writer, catalyzes ac4C on rRNA, tRNA, and potentially mRNA, thereby regulating RNA stability and translation efficiency. Accumulating evidence indicates that NAT10-mediated ac4C influences skeletal homeostasis through several distinct routes. It promotes osteogenic differentiation of BMSCs by stabilizing RUNX2 mRNA, drives osteoclastogenesis through Fos/NFATc1 signaling, and modulates inflammation in periodontitis and rheumatoid arthritis. It further promotes osteoarthritis by suppressing chondrogenic programs and fuels osteosarcoma through metabolic reprogramming. Pharmacological NAT10 inhibition with Remodelin shows therapeutic potential in preclinical models, although its specificity remains incompletely characterized. SIGNIFICANCE NAT10-mediated ac4C modification represents an emerging regulatory mechanism in skeletal biology. Accumulating evidence supports its involvement in osteoporosis, inflammatory bone loss, osteoarthritis, and osteosarcoma through effects on RNA stability, translation efficiency, and downstream signaling. Substantial gaps nonetheless remain. In particular, it is still unclear how ac4C on specific transcripts controls bone- and cartilage-cell function, and to what extent these modifications are dynamically regulated across disease states.