RNA cytosine modifications regulates musculoskeletal disorders

The RNA cytosine modification (RCM), particularly 5-methylcytosine (m⁵C) and N4-acetylcytidine (ac⁴C) modification, represents a rapidly advancing frontier in recent epitranscriptomic research. These reversible modifications intervene in the process of RNA generation, thus playing a critical role in the post-transcriptional regulation of RNA, including nuclear export, ribosome assembly, translation, and stability, thereby modulating various fundamental biological processes, such as cellular proliferation, differentiation, and cell death. Musculoskeletal disorders (MSDs), including osteoarthritis (OA), osteoporosis (OP), rheumatoid arthritis (RA), osteosarcoma (OS), and intervertebral disc degeneration (IVDD), are a major class of debilitating conditions that affect the locomotor system. Emerging evidence has demonstrated that dysregulation of m⁵C or ac⁴C modification contributes significantly to MSD pathogenesis through multiple mechanisms, including chondrocyte pyroptosis, lipid droplet dynamics, macrophage polarization, osteogenic and osteoclastic differentiation, synovial hyperplasia and invasion, and tumor-associated metabolic reprogramming. Moreover, these modifications are mechanistically linked to key pathological hallmarks, such as immune cell infiltration, ferroptosis, autophagy, and aberrant mechanical compression transduction. Pharmacological targeting of m⁵C- and ac⁴C-regulatory enzymes has been indicated to have therapeutic potential in animal models of MSDs. Herein, we present this review that systematically addresses the molecular basis and current knowledge on the mechanisms underlying RCMs in a variety of MSDs, along with translational strategies targeting these epitranscriptomic pathways. Finally, we present our thoughts and comments on this topic.