Rhabdomyosarcoma, the most common soft tissue sarcoma in children, poses significant research challenges due to its diverse subtypes, anatomical locations, and cellular origins. While advances have been made in understanding its complex genetic landscape—including chromosomal translocations, gene mutations, and factors linked to skeletal muscle development—many questions remain unresolved. Future studies should focus on elucidating the molecular mechanisms driving the fate of rhabdomyosarcoma progression and refining its genomic profile. Such efforts will provide a critical foundation for developing personalized prevention and therapeutic strategies for rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, characterized by high heterogeneity and strong invasiveness. The occurrence and progression of RMS involve multiple epigenetic regulatory mechanisms, including DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation. These epigenetic alterations influence tumor initiation, maintenance, metastasis, and drug resistance by modulating gene expression and key signaling pathways. Typical epigenetic regulatory targets include the BET protein family, histone deacetylases (HDACs), and EZH2. Epigenetic drugs developed against these targets have already shown promising activity in preclinical studies and early-phase clinical trials. In addition, combination strategies are gaining increasing attention, such as the use of EZH2 or HDAC inhibitors together with chemotherapy, differentiation inducers, or immune checkpoint inhibitors, which can enhance efficacy and overcome resistance. Future research directions will rely on integrative multi-omics approaches and cutting-edge technologies to overcome the limitations of current models and datasets, thereby uncovering novel mechanisms of epigenetic regulation in RMS. By integrating precision medicine with multi-omics insights, it will be possible to identify new biomarkers and potential targets, providing a foundation for the development of personalized epigenetic therapies and ultimately improving the clinical management of pediatric RMS.

Rhabdomyosarcoma (RMS) is one of the most common malignant soft-tissue tumors in children and adolescents, characterized by a blockade of skeletal-muscle differentiation. Here we summarize basic studies and key advances in the field. We cover three aspects in RMS: differentiation control, cell-cycle regulation, and signaling networks. During early differentiation, Myogenic Differentiation 1 (MyoD) heterodimerizes with E-proteins and initiates muscle-lineage gene programs together with muscle-specific miR-206 and selected lncRNAs. During late differentiation, Myogenin orchestrates myoblast fusion and myotube maturation, while its activity and stability are modulated by upstream regulators including the miR-1-TRPS1 axis, Arp5, and IL-4/STAT6. At the cell-cycle level, the p21/p27 and Rb-E2F axes promote G₁ arrest to license differentiation. When these signaling pathways are disrupted, tumor cells maintain high proliferative activity, but cell differentiation is blocked. At the signaling level, aberrant activation of PI3K/AKT/mTOR and MAPK/ERK, together with differentiation-suppressive pathways such as Notch and Hedgehog, interconnect to form a self-sustaining “proliferation-de-differentiation” loop. Mechanistically informed strategies—including inhibition of aberrant pathways, correction of epigenetic and non-coding RNA imbalances, restoration of MyoD/Myogenin function, and CRISPR-based precision interventions—show potential to induce differentiation and restrain tumor progression. Remaining challenges include unclear causal relationships among pathways and subtype-specific drivers, a paucity of predictive biomarkers, and insufficient definition of therapeutic windows and resistance dynamics for combination regimens. Future work should leverage single-cell and spatial omics to integrate epigenetic and post-transcriptional layers, reconstruct actionable differentiation networks, and—under biomarker guidance—develop and stratify cross-pathway combination strategies to advance RMS differentiation therapy toward precision and clinical translation.

Rhabdomyosarcoma is the most common soft tissue sarcoma in children, and its primary cause lies in the impaired differentiation of skeletal muscles. The development of skeletal muscles is dynamically regulated by multiple factors, which form core regulatory circuits predominantly governed by muscle-specific enhancers. Once erroneous enhancer connections occur, they will unlock phenotypic plasticity, causing cells to deviate from their normal differentiation path and enter an abnormal proliferative state, ultimately forming rhabdomyosarcoma. This process requires the coordinated action of chromatin remodeling factors. Additionally, as a pediatric tumor, rhabdomyosarcoma has a low mutational burden. It is precisely this non-mutational epigenetic reprogramming that unlocks phenotypic plasticity in the normal skeletal muscle differentiation process, thereby leading to the development of rhabdomyosarcoma. This article summarizes the role of epigenetic regulation during the onset and progression of rhabdomyosarcoma, with a focus on analyzing DNA methylation, histone methylation, acetylation, non-coding RNAs (such as miRNA, lncRNA, circRNA, and eRNA), chromatin remodeling, and RNA modifications, aiming to lay a theoretical foundation for the prevention and treatment of rhabdomyosarcoma.