Psoriasis is an incurable and recurrent skin disease, and the need to develop new strategies for the treatment of psoriasis persists. Smilax glabra Roxb. (SGR) is listed as a key traditional Chinese medicine for the treatment of psoriasis through medicinal bath therapy in "Guideline for the diagnosis and treatment of psoriasis in China"; the active ingredients responsible for its anti-psoriatic effects and their mechanisms of action still require in-depth research. In this study, we first found that the topical application of SGR extract showed an anti-psoriasis effect in mice by using IMQ-induced primary and recurrent psoriasis mouse model. Network pharmacology, molecular docking, supercoiled DNA relaxation assay, luciferase reporter gene assay, and animal pharmacodynamics revealed that astilbin, quercetin, and resveratrol were key anti-psoriatic compounds in SGR extract for treating psoriasis by inhibiting TOP2A and activating AhR. These findings suggested that the synergistic effect of TOP2A inhibition and AhR activation was the key mechanism of SGR for the treatment of psoriasis. The combination of AhR activation and TOP2A inhibition synergistically alleviated psoriasis-like lesions and ameliorated the relapse of psoriasis-like lesions in mice. AhR activation and TOP2A inhibition synergistically regulated the cytokine-cytokine receptor interaction pathway and keratinization progress to prevent the relapse of psoriasis. This study investigates the "multi-component, multi-target" mechanism of SGR in treating psoriasis from the perspective of the interaction between targets, providing a new strategy for psoriasis topical treatment: the combination of TOP2A inhibitors and AhR activators.
