Targeting the epigenetic regulator bromodomain-containing protein 4 by BRD4 siRNA lipoplexes and PFI-1 in psoriasis.

Psoriasis is a chronic skin disease characterized by keratinocyte hyperproliferation, epidermal hyperplasia, and immune cell infiltration involving both innate and adaptive immune systems. Bromodomain-containing protein 4 (BRD4), part of the Bromodomain and Extra-Terminal (BET) family, is implicated in various inflammatory and hyperproliferative disorders, though its role in psoriasis is unclear. This study investigates BRD4's role in psoriasis pathogenesis using BRD4-specific small interfering RNA (siRNA) lipoplexes (BRD4-siRNA-LP) and the small molecule inhibitor PFI-1. BRD4's effect was analyzed in human macrophages through gene-specific knockout and overexpression. Transfection of pcDNA5-Flag-BRD4-WT in macrophages activated core inflammatory regulators, while BRD4 disruption via BRD4-siRNA and BRD4 p5188 pSUPER-shRNA inhibited inflammation-related gene transcription. Topical application of BRD4-siRNA-LP and PFI-1 on Imiquimod (IMQ)-treated mice significantly reduced psoriatic plaques and epidermal hyperplasia. BRD4 inhibition notably downregulated pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, TGF-β, and TNF-α. Both in vitro and in vivo findings showed that BRD4 suppression significantly decreased the expression of signaling proteins including p65 NF-κB, MAPKs, and STAT3. Furthermore, BRD4 was found to interact with p65 NF-κB and STAT3, and its inhibition disrupted these protein-protein interactions. Inhibiting BRD4 with BRD4-siRNA-LP and PFI-1 effectively alleviates experimental psoriasis symptoms, making it a promising target for therapeutic intervention in psoriasis.