Background: Psoriasis is a chronic autoimmune condition characterized by recurrent episodes of skin inflammation. Despite progress in treatment, managing flare-ups of psoriasis remains a significant hurdle once the therapy is halted. This review aims to unravel the enigma of relapse by examining the interactions between epigenetics, metabolic reprogramming, and inflammatory memory.Methods and Results: Skin-resident memory T cells and keratinocytes with a history of inflammation play crucial roles in the metabolic and epigenetic alterations observed during relapse. This review explores epigenetic factors involved in the recurrence of psoriasis, such as histone alterations, chromatin restructuring, and non-coding RNAs. Furthermore, we explored environmental influences, metabolic reprogramming, and genetic predispositions that influence the persistence and recurrence of psoriasis. We also outline the function of the gut-brain-skin axis in this scenario. Finally, we discuss pharmacological strategies for managing psoriasis relapse, including targeted biologics.Conclusion: This review provides a comprehensive summary on the intricate epigenetic, molecular, metabolic and environmental cues that exacerbate or facilitate psoriasis relapse. In summary, it also provides an enticing update on the therapeutics currently employed to treat psoriasis relapse.
