Harnessing Quinone Derivatives from Rubia cordifolia for Topical Therapy: Unveiling Structure-Activity and Structure-Permeation Relationships to Suppress Psoriasiform Inflammation

Rubia cordifolia is a medicinal herb with anti-inflammatory activity. The key active ingredients of R. cordifolia responsible for its antipsoriatic activity and the underlying mechanisms are not fully understood. The present study was designed to investigate the anti-inflammatory activity of quinones in R. cordifolia against psoriasis. The quinones tested were alizarin, purpurin, and mollugin. Aloe-emodin, a model anthraquinone, was used as a positive control. Compared with the control, the quinones significantly reduced cytokine/chemokine overexpression in tumor necrosis factor (TNF)-α-activated keratinocytes. This reduction was also detected in imiquimod (IMQ)-stimulated macrophages. Quinones exerted anti-inflammatory effects through the Janus kinase (JAK)1/signal transducer and activator of the transcription (STAT)3 signaling pathway. Network pharmacology revealed that quinones targeted some proteins associated with psoriasis-related pathways, such as glycosylphosphatidylinositol (GPI)-anchored protein synthesis for alizarin. The key targets of various compounds were quite different. Alizarin showed greater absorption into intact and inflammation-simulated skin than the other quinones based on an in vitro permeation test (IVPT). In silico molecular docking predicted that stratum corneum (SC) ceramide II is important for governing the skin delivery of quinones. The in vivo IMQ-sensitized psoriasiform mouse model showed a significant mitigation of psoriasis-like lesions following the topical delivery of alizarin. Alizarin also suppressed cytokines/chemokines and restored skin barrier function in lesional skin, leading to the blockade of keratinocyte hyperproliferation and macrophage/neutrophil recruitment. The average epidermal thickness was decreased from 116 to 78 μm by alizarin. Our findings revealed the therapeutic potential of anthraquinones from R. cordifolia against psoriasiform inflammation.