Histone modifications in skin fibrosis: linking immune dysregulation, metabolic reprogramming, and persistent fibrotic remodeling.

Skin fibrosis encompasses a spectrum of disorders, including hypertrophic scars, keloids, systemic sclerosis and lymphedema, that arise from distinct initiating insults but converge on persistent fibroblast activation, immune dysregulation and excessive extracellular matrix deposition. Although inflammatory, metabolic and mechanical abnormalities are increasingly recognized in these diseases, the mechanisms through which these signals are integrated into sustained profibrotic transcriptional programs remain incompletely understood. Histone modifications provide a dynamic and potentially reversible regulatory layer that links changes in the tissue microenvironment to chromatin accessibility and gene expression. In this Review, we summarize the major classes of histone modifications implicated in skin fibrosis, including acetylation, methylation, lactylation and selected non-canonical modifications. We discuss how their writers, erasers and readers regulate fibroblast activation, immune-cell dysfunction and profibrotic signaling pathways, and compare the available evidence across pathological scars, systemic sclerosis and lymphedema. Current evidence is most extensive for acetylation-related mechanisms, whereas the effects of histone methylation are highly dependent on the modified locus, cell type and experimental context. Histone lactylation provides an emerging mechanistic link between glycolytic reprogramming, lactate accumulation and profibrotic transcription, although its broader importance across cutaneous fibrotic diseases remains to be established. We further evaluate inconsistencies among experimental studies, limitations in causal interpretation and the translational challenges associated with targeting histone-modifying enzymes and chromatin readers. These challenges include limited cell-type specificity, non-histone effects, systemic toxicity and inadequate delivery to fibrotic tissues. Future integration of longitudinal, cell-resolved and spatial epigenomic approaches may help define disease-specific chromatin programs and facilitate the development of more precise biomarkers and targeted antifibrotic therapies.