{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T10:24:16Z","timestamp":1787135056944,"version":"build-2736575974"},"reference-count":57,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2026 \u201cBuilding Dreams, Setting Sail\u201d Open Cooperation Fund for Scientific Research"},{"name":"Songgang People\u2019s Hospital, Bao\u2019an District, Shenzhen","award":["SGYYZ2026B05"],"award-info":[{"award-number":["SGYYZ2026B05"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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\u2019s 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-1\u03b2, 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 \u22126.0 to \u22127.8 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.<\/jats:p>","DOI":"10.3390\/ijms27167109","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T09:24:53Z","timestamp":1786353893000},"page":"7109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Shikonin-Loaded Nanoparticles Ameliorate DEHP-Exacerbated Psoriasis Skin Injury via Targeted Inhibition of the p38 MAPK Signaling Pathway"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5052-148X","authenticated-orcid":false,"given":"Qinghua","family":"Tang","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Centre, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixiong","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Centre, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Centre, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Centre, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Bie","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Centre, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesong","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Centre, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4318-5132","authenticated-orcid":false,"given":"Lin","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Centre, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9981-0270","authenticated-orcid":false,"given":"Ming","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Centre, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alajroush, W.A., Alrshid, A.I., Alajlan, A.H., Alsalamah, Y.B., Alhumaidan, M.I., Alhoumedan, A.I., Alrasheed, M.I., Alowairdhi, Y.A., Alowirdi, F., and Aljoufi, A.Z. 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