Therapeutic implications of epigenetic alterations in burns: a new frontier in burn medicine

Epigenetic modifications refer to heritable changes in gene expression that occur without alterations to the DNA sequence. The earliest evidence of DNA methylation-a key epigenetic mechanism-existed before Watson and Crick described the DNA double helix. Main forms of epigenetic regulation include DNA methylation, histone modifications, and mechanisms mediated by non-coding RNA. DNA methylation, which mainly happens at cytosine residues within cytosine-phosphate-guanine dinucleotides, is usually linked to transcriptional repression. Histone modifications, such as acetylation, methylation, and phosphorylation, affect chromatin structure and thereby alter transcriptional access. Simultaneously, non-coding RNAs like microRNAs and long non-coding RNAs regulate gene expression through transcriptional and post-transcriptional pathways. Abnormal epigenetic regulation has been strongly connected to the development of various human diseases, including cancers, diabetes mellitus, cardiovascular diseases, and neurodegenerative disorders. Recent evidence now points to epigenetic dysregulation as a key factor in the systemic and localized responses to severe burn injuries. These modifications control inflammatory signaling, immune cell polarization, and wound-healing processes. For example, DNA methylation and histone alterations in macrophages influence the balance between pro- and anti-inflammatory pathways, angiogenesis, and tissue regeneration. Additionally, severe burns are recognized as significant accelerators of epigenetic aging, with a direct link between injury severity and biological age advancement. However, the full extent of epigenetic roles in post-burn physiological changes remains poorly understood. The present review aims to explore these mechanisms and provide an insight into the complex network of factors shaping the pathophysiological response to these modifications post-burn injury.