Potential Targets and Mechanisms of Saikosaponin D in Psoriasis: A Bioinformatic and Experimental Study on Oxidative Stress.

Objective: This study aims to explore the potential therapeutic effect of Saikosaponin D (SSD) on psoriasis and elucidate its underlying mechanisms, focusing on oxidative stress modulation and immune regulation. Methods: Network pharmacology, machine learning (LASSO, SVM-RFE, Random Forest), and molecular dynamics identified Saikosaponin D's core targets (STAT3, CCNB1) in psoriasis. Differential gene analysis (GEO datasets GSE6710, GSE50790, GSE14905), WGCNA, and PPI networks screened Saikosaponin D-psoriasis-oxidative stress intersecting genes. In vivo validation employed an imiquimod-induced psoriasis mice model with Saikosaponin D (2 mg/kg/day). Histology, qPCR, Western blot, and immune infiltration (CIBERSORT) assessed SAIKOSAPONIN D's effects on inflammation, JAK2/STAT3 signaling, and oxidative stress markers (GPX4, SLC7A11). Results: Saikosaponin D markedly alleviated psoriasis-like symptoms, diminishing epidermal thickness and keratinocyte proliferation, accompanied by reduced Ki67 expression. Bioinformatics investigation revealed 25 intersecting genes, with STAT3 and CCNB1 identified as principal targets. Molecular docking revealed that Saikosaponin D consistently binds to STAT3 and CCNB1, with binding energies of -8.3 and -9.0 kcal/mol, respectively. Saikosaponin D suppressed JAK2/STAT3 phosphorylation, leading to the downregulation of IL-1, IL-6, and TNF-α expression. Saikosaponin D enhanced GPX4 expression and reduced SLC7A11 levels, restoring oxidative equilibrium. Moreover, Saikosaponin D regulated immune infiltration by reducing M1 macrophages and augmenting Tregs, hence enhancing the psoriatic immune microenvironment. Conclusion: Saikosaponin D suppresses psoriasis by dual-targeting STAT3/CCNB1, disrupting JAK2/STAT3 signaling and oxidative stress. This study provides new insights into the mechanism of Saikosaponin D in psoriasis, offering a promising multi-pathway therapeutic candidate.