Epigenetic Therapies for Inflammatory and Immune-Mediated Skin Diseases.

Inflammatory and immune-mediated skin diseases are increasingly recognized as disorders in which genetic susceptibility is shaped and sustained by environmentally responsive regulatory programs. Psoriasis, atopic dermatitis (AD), vitiligo, systemic sclerosis (SSc), lupus erythematosus (LE), and lichen planus (LP) are clinically distinct, yet they share chronic or relapsing inflammation, tissue remodeling, and limited durability of many current therapies. Because genetic variation alone cannot fully explain disease onset, flare dynamics, heterogeneity in severity, or lesion recurrence, epigenetic mechanisms have emerged as a plausible link between environmental exposures and stable disease phenotypes in skin. Epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNA networks, controls cell-type-specific transcription without altering the DNA sequence and may contribute to persistent inflammatory states and disease memory despite clinical improvement. The current review synthesizes primary preclinical and translational evidence on epigenetic-targeted therapeutic strategies across these conditions, focusing on interventions that modulate DNA methylation, histone acetylation and deacetylation, histone methylation, chromatin-associated regulatory proteins, and RNA-based approaches. We compare the maturity of therapeutic development across diseases, noting that research and intervention studies are concentrated in psoriasis and AD, whereas evidence for vitiligo, SSc, LE, and LP remains more limited and often derived from systemic or non-cutaneous models. Finally, we outline key gaps that currently restrict clinical translation and discuss why bridging them is essential for determining whether epigenetic modulation can move beyond proof-of-concept toward durable and clinically actionable interventions in inflammatory skin disease.