Shikonin-Loaded Nanoparticles Ameliorate DEHP-Exacerbated Psoriasis Skin Injury via Targeted Inhibition of the p38 MAPK Signaling Pathway.

Di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous environmental plasticizer, has been increasingly linked to the exacerbation of inflammatory skin conditions, especially psoriasis. However, the mechanisms and effective therapeutic strategies targeting DEHP-aggravated psoriasis remain elusive. We integrated network toxicology, network pharmacology, and molecular docking to explore the targets of DEHP-exacerbated psoriasis and the protective effects of shikonin (SH). These findings were validated in a DEHP/IMQ-induced mouse model using a novel shikonin nanoparticle (SH-NP) that overcomes SH's inherent hydrophobicity. Computational analyses revealed that SH counteracts DEHP skin toxicity through a multi-target network, identifying the p38 mitogen-activated protein kinase (p38 MAPK), TNF, IL-1β, proliferating cell nuclear antigen (PCNA), and matrix metalloproteinases 2 and 9 (MMP2/9) as core therapeutic nodes. Molecular docking verified this network, revealing robust binding between SH and key targets with binding energies ranging from -6.0 to -7.8 kcal/mol, consistently outperforming DEHP. In vivo experiments demonstrated that topical application of SH-NP significantly ameliorated macroscopic skin injury and reduced PASI scores. Mechanistically, SH-NP effectively reversed the DEHP-exacerbated inflammatory microenvironment by decreasing macrophage and mast cell infiltration in the dermis, reducing pro-inflammatory cytokine levels, and inhibiting the phosphorylation of p38 MAPK. Furthermore, SH-NP treatment successfully suppressed keratinocyte hyperproliferation, as evidenced by downregulated PCNA expression and reduced epidermal thickness. SH-NPs also markedly downregulated the elevated levels of MMP2/9 in mice, thereby mitigating collagen degradation and maintaining dermal matrix integrity. This study shows that SH-NPs alleviate DEHP-aggravated psoriasis by suppressing local inflammation, keratinocyte hyperproliferation, and collagen degradation, offering a targeted nanostrategy for environmentally exacerbated skin diseases.