Inhibition of HaCaT Proliferation and Imiquimod-Induced Psoriasis by Calcipotriol Through Regulation of the Glutathione/Glutathione Peroxidase 4 Pathway

Abstract

Psoriasis is a chronic and recurrent skin disease characterized by aberrant proliferation and differentiation of keratinocyte cells. Although calcipotriol has been employed in the clinical management of psoriasis, no association between the anti-inflammatory mechanism and iron death has been reported. Therefore, we assume that calcipotriol may down-regulate cell activity and suppress the expression of tissue inflammatory factors by regulating the glutathione (GSH) and glutathione peroxidase 4 (GPX4) pathway, thereby alleviating tissue inflammation and ameliorating psoriasis symptoms. The experimental groups consisted of a control group, a model group, a Calcipotriol group, and a Calcipotriol+Ferrostatin-1 group. In vitro experiments, a lipopolysaccharides-induced HaCaT cell model was established. In vivo experiments, an imiquimod-induced psoriasis mice model was constructed. The results showed that calcipotriol effectively downregulated the expression of GPX4 and GSH, thereby inhibiting HaCaT cell proliferation through modulation of Ki-67 protein expression and DNA breakage. Ferrostatin-1 could partially reverse these effects. Additionally, calcipotriol downregulated the expression of GPX4 and GSH in skin tissues and upregulated the expression of long-chain acyl-CoA synthetase 4 by suppressing the levels of SLC7A11 and ferritin, leading to promote the accumulation of ROS and ferroptosis. Moreover, calcipotriol demonstrated inhibitory effects on the inflammatory mediators and attenuated skin inflammation. Therefore, calcipotriol effectively ameliorated psoriatic lesions. In conclusion, this study revealed that calcipotriol exerts its therapeutic potential by promoting cellular clearance and suppressing tissue inflammation through upregulation of ferroptosis progression. Therefore, this study provides new therapeutic drugs and functions for the treatment of psoriasis.