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<p>Psoriasis is a chronic immune-mediated skin disease characterized by keratinocyte hyperproliferation and persistent inflammation driven by cytokines signaling. This study aimed to identify novel anti-psoriasis natural products and evaluate their potential molecular attributes. Transcriptomics analysis of psoriatic lesions (GSE54456) and in vitro IL-17A-stimulated HaCaT keratinocytes demonstrated significant upregulation of the lysine methyltransferase SMYD2, suggesting its possible involvement in psoriasis pathology. Treatments of HaCaT cells in vitro with the olive tree (<i>Olea europaea</i>) fruit oil phenolics <i>S</i>-(–)-oleocanthal (OC), <i>S</i>-(–)-hydroxy-oleocanthal (HOC, oleacein), and <i>S</i>-(–)-ligstroside aglycone (LA) at a single 10 µM treatment concentration significantly suppressed the SMYD2 expression and reduced markers of psoriatic inflammation, validated by quantitative PCR and Western blot analysis. The RAW 264.7 macrophages stimulated with LPS and IFN-γ exhibited diminished expression of the pro-inflammatory cytokines, including iNOS, IL-6, and TNF-α, following OC, HOC, and LA treatments. Molecular and protein-protein interaction modeling identified the IL-17A dimer selective binding pocket where OC displayed near-benchmark complementarity binding to the co-crystallized ligand (PubChem CID 153616520), engaging key residues Gln94, Trp67, and Leu97. OC induced the largest pocket expansion (1.52-fold) among all ligands, suggesting strong allosteric interference with IL-17RA binding. Consistently, AlphaLISA assays confirmed the OC ability to effectively inhibit the IL-17A–IL-17RA interaction, unlike LA, which showed modest inhibition. Further, surface plasmon resonance demonstrated dose-dependent blockade of IL-17A–IL-17F binding by OC, validating its IL-17A-IL-17F protein-protein heterodimerization interaction inhibitory capacity. Collectively, findings identify OC as a potent natural modulator for the IL-17 signaling that downregulates SMYD2 and disrupts IL-17A protein-protein interactions, evidencing its anti-psoriatic therapeutic potential.</p> Graphical abstract <p></p>

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Olive (Olea europaea) phenolics for the control of psoriasis via targeting SMYD2 and IL-17A protein–protein interaction networks

  • 期刊论文

  • 发表日期：

    2026年3月9日

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  • Md Ashiq Mahmud,
  • Mohamed M. Mohyeldin,
  • Md Towhidul Islam Tarun,
  • Abu Bakar Siddique,
  • Sitanshu S. Singh,
  • Khalid A. El Sayed

摘要

Psoriasis is a chronic immune-mediated skin disease characterized by keratinocyte hyperproliferation and persistent inflammation driven by cytokines signaling. This study aimed to identify novel anti-psoriasis natural products and evaluate their potential molecular attributes. Transcriptomics analysis of psoriatic lesions (GSE54456) and in vitro IL-17A-stimulated HaCaT keratinocytes demonstrated significant upregulation of the lysine methyltransferase SMYD2, suggesting its possible involvement in psoriasis pathology. Treatments of HaCaT cells in vitro with the olive tree (Olea europaea) fruit oil phenolics S-(–)-oleocanthal (OC), S-(–)-hydroxy-oleocanthal (HOC, oleacein), and S-(–)-ligstroside aglycone (LA) at a single 10 µM treatment concentration significantly suppressed the SMYD2 expression and reduced markers of psoriatic inflammation, validated by quantitative PCR and Western blot analysis. The RAW 264.7 macrophages stimulated with LPS and IFN-γ exhibited diminished expression of the pro-inflammatory cytokines, including iNOS, IL-6, and TNF-α, following OC, HOC, and LA treatments. Molecular and protein-protein interaction modeling identified the IL-17A dimer selective binding pocket where OC displayed near-benchmark complementarity binding to the co-crystallized ligand (PubChem CID 153616520), engaging key residues Gln94, Trp67, and Leu97. OC induced the largest pocket expansion (1.52-fold) among all ligands, suggesting strong allosteric interference with IL-17RA binding. Consistently, AlphaLISA assays confirmed the OC ability to effectively inhibit the IL-17A–IL-17RA interaction, unlike LA, which showed modest inhibition. Further, surface plasmon resonance demonstrated dose-dependent blockade of IL-17A–IL-17F binding by OC, validating its IL-17A-IL-17F protein-protein heterodimerization interaction inhibitory capacity. Collectively, findings identify OC as a potent natural modulator for the IL-17 signaling that downregulates SMYD2 and disrupts IL-17A protein-protein interactions, evidencing its anti-psoriatic therapeutic potential.

Graphical abstract