@article{Fu2026, 
author = {Yuan Fu and Xuling Tan and Lixia Qin and Chunyu Wang},
title = {From inactivation to intervention: X chromosome silencing in disease pathogenesis and emerging therapeutic strategies},
year = {2026},
journal = {Genes & Diseases},
volume = {13},
number = {5},
keywords = {Detection of X chromosome inactivation, Mechanisms, The inactive X chromosome reactivation, Therapeutic strategies, X chromosome inactivation},
url = {https://www.sciopen.com/article/10.1016/j.gendis.2025.101964},
doi = {10.1016/j.gendis.2025.101964},
abstract = {X chromosome inactivation (XCI) is a crucial epigenetic mechanism that balances X-linked gene expression in females via random silencing of one X chromosome. Skewed XCI—non-random inactivation favoring one allele—impacts disease penetrance in X-linked disorders. In heterozygous females, phenotypic severity correlates with XCI skewing degree. Accurate XCI quantification is critical for predicting clinical variability and improving risk assessment in X-linked mutation carriers. The X inactivation-specific transcript (Xist) gene drives XCI initiation through its long non-coding RNA (lncRNA) that recruits polycomb repressive complexes 2 (PRC2) to establish stable heterochromatin. Bracingly, emerging therapies leveraging XCI reactivation (e.g., Xist RNA inhibition, Xist RNA epigenetic modification) show preclinical potential to rescue silenced alleles, advancing treatment strategies for X-linked diseases. This review synthesizes XCI mechanisms, current skewing detection methods, and therapeutic developments, providing a roadmap for clinical translation of XCI-targeted interventions.}
}