Epigenetic orchestration of RNA m⁶A methylation in wound healing and post-wound events

Skin, the largest human organ, demonstrates remarkable regenerative capacity through spatiotemporally coordinated healing processes. Chronic wounds, including diabetic ulcers and burn injuries pose significant clinical challenges due to persistent inflammation, impaired angiogenesis, defective appendage regeneration, and pathological scarring. Emerging evidence reveals N⁶-methyladenosine (m⁶A) methylation - the most prevalent RNA modification - as a critical regulator of wound healing and tissue remodeling. The m⁶A machinery (writers, readers, erasers) dynamically controls RNA stability, translation, and splicing, thereby modulating keratinocyte migration, fibroblast activation, macrophage polarization, and stem cell differentiation. Dysregulated m⁶A dynamics impair diabetic wound healing through oxidative stress amplification and autophagy deficiency, while disrupting critical repair pathways in burn injuries. Aberrant m⁶A modifications exacerbate pathological scarring and dysfunctional appendage regeneration via dysregulated extracellular matrix deposition and fibroblast dysfunction. Current understanding of m⁶A spatiotemporal regulation and clinical potential remains fragmented despite significant advances. Future investigations integrating single-cell sequencing, spatial transcriptomics, and multidisciplinary approaches are crucial to decode the multifaceted roles of m⁶A, enabling the development of novel epitranscriptome-targeted therapies for chronic wound management and functional skin regeneration. The review systematically examines m⁶A-mediated mechanisms in cutaneous repair and remodeling, providing strategic insights for advancing regenerative medicine.