Epigenetic regulation of Hutchinson-Gilford progeria syndrome: from molecular mechanisms to targeted interventions

Aging is a major determinant of human lifespan and health, driven in part by epigenetic dysregulation, including alterations in DNA methylation patterns, histone modifications, chromatin structure, and non-coding RNA (ncRNA) networks. Hutchinson-Gilford progeria syndrome (HGPS), a rare disorder characterized by premature aging due to mutations in the LMNA gene, is an ideal model for studying epigenetic changes related to aging. HGPS cells exhibit hallmark epigenetic abnormalities, such as global DNA hypomethylation, heterochromatin loss, disruption of lamina-associated domains (LADs), and imbalances in non-coding RNA networks, and dysregulation of RNA modifications, all of which contribute to genomic instability, inflammation, and cellular dysfunction. In recent years, epigenetic-targeted interventions, including farnesyltransferase inhibitors (e.g., lonafarnib), histone deacetylase (HDAC) inhibitors, and CRISPR-based gene editing, have shown promise in preclinical studies for reversing progeroid phenotypes, with some therapies progressing to clinical trials. This review systematically explores the epigenetic regulatory mechanisms underlying HGPS and their implications for aging, while summarizing recent advances in epigenetic-based therapeutic strategies. A deeper understanding of the epigenetic landscape of aging may pave the way for novel therapeutic approaches to HGPS and age-related diseases.