Sinomenine Suppressed Keratinocyte Proliferation and Imiquimod-Induced Psoriasis-Like Dermatitis by Regulating lncRNA XIST.

Background: Psoriasis is a chronic inflammatory skin disease. Sinomenine (SIN) has anti-inflammatory and antioxidant effects.

Objective: The objective of this study was to confirm the anti-inflammatory effects and mechanism of SIN in imiquimod (IMQ)-induced psoriasis-like mouse model and IMQ-induced differentiated human keratinocytes (HaCaT) cells.

Methods: BALB/c mice were treated with IMQ to construct a psoriasis-like mice model. PASI score and HE staining were used to observe pathology injury of skin tissue. The secretion of inflammatory factors and the oxidative stress level were detected by ELISA. HaCaT cells after induction of differentiation were treated with IMQ (100 μM) and SIN (10 μg/mL or 50 μg/mL), cell viability, the secretion of inflammatory factors, and the oxidative stress level were detected by MTT assay, ELISA, respectively. The expression of lncRNA XIST was detected by RT-qPCR. The relationship between XIST and EIF4G2 protein was detected by RNA immunoprecipitation (RIP) assay and ubiquitination experiment.

Results: SIN significantly reduced PASI score, epidermal thickness, inflammatory response, and oxidative stress levels that increased by IMQ in vivo. SIN inhibited IMQ-induced HaCaT cell proliferation, inflammatory response, and oxidative stress levels and decreased the expression of XIST. Overexpression of XIST negated the protective effect of SIN on HaCaT cells. XIST interacted directly with EIF4G2 and regulated EIF4G2 expression via K48 ubiquitin. Knockdown of XIST reduced the half-life of EIF4G2 and decreased EIF4G2 protein stability. In addition, the E3 ubiquitin protein ligase MDM2 interacted with EIF4G2 and downregulated EIF4G2 expression. XIST reduced the interaction between MDM2 and EIF4G2, which mediated EIF4G2 K48 ubiquitination. Overexpression of XIST negated the protective effect of SIN on the inflammation of HaCaT cells through activating the NF-κB signaling pathway, while NF-κB pathway inhibitor PDTC reversed this result.

Conclusion: SIN had a protective effect on psoriasis and could inhibit HaCaT cell proliferation and inflammatory response via XIST/MDM2/EIF4G2/NF-κB axis.