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<p>Skin pigmentation disorders involve complex biological regulation, with tyrosinase (TYR) and melanocortin 1 receptor (MC1R) serving as key therapeutic targets. Through molecular docking screening of 389 natural compounds, we identified isorhamnetin-3-O-neohespeidoside as a potent dual inhibitor, demonstrating superior binding affinities (-8.001&#xa0;kcal/mol for TYR and − 7.342&#xa0;kcal/mol for MC1R) compared to arbutin (reference compound). Subsequent in vitro validation revealed that isorhamnetin-3-O-neohespeidoside (8 µM) significantly inhibited TYR activity by 44.42% (<i>p</i> &lt; 0.0001) and reduced MC1R expression by 33.39% (<i>p</i> &lt; 0.0001) in B16 melanoma cells, while maintaining &gt; 85% cell viability (IC<sub>50</sub> = 52.22 µM). The compound also decreased melanin content by 38.7% (<i>p</i> &lt; 0.0001) and upregulated LC3-II expression (2.1-fold vs. control, <i>p</i> &lt; 0.0001), indicating enhanced autophagy. These results demonstrate that isorhamnetin-3-O-neohespeidoside, a flavonoid glycoside from Typhae Pollen, acts through multiple mechanisms - direct enzyme inhibition, receptor downregulation, and autophagy induction - making it a promising natural candidate for hyperpigmentation treatment. Our integrated approach combining computational screening with experimental validation provides a robust framework for identifying multi-target depigmenting agents.</p>

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Natural dual inhibitor isorhamnetin-3-O-neohespeidoside targets tyrosinase and MC1R for skin pigmentation management

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月21日

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  • Rongrong Deng,
  • Shiqian Zheng,
  • Shengjun Xie,
  • Gengjiu Huang,
  • Zhiwen Ou,
  • Zhibin Shen

摘要

Skin pigmentation disorders involve complex biological regulation, with tyrosinase (TYR) and melanocortin 1 receptor (MC1R) serving as key therapeutic targets. Through molecular docking screening of 389 natural compounds, we identified isorhamnetin-3-O-neohespeidoside as a potent dual inhibitor, demonstrating superior binding affinities (-8.001 kcal/mol for TYR and − 7.342 kcal/mol for MC1R) compared to arbutin (reference compound). Subsequent in vitro validation revealed that isorhamnetin-3-O-neohespeidoside (8 µM) significantly inhibited TYR activity by 44.42% (p < 0.0001) and reduced MC1R expression by 33.39% (p < 0.0001) in B16 melanoma cells, while maintaining > 85% cell viability (IC50 = 52.22 µM). The compound also decreased melanin content by 38.7% (p < 0.0001) and upregulated LC3-II expression (2.1-fold vs. control, p < 0.0001), indicating enhanced autophagy. These results demonstrate that isorhamnetin-3-O-neohespeidoside, a flavonoid glycoside from Typhae Pollen, acts through multiple mechanisms - direct enzyme inhibition, receptor downregulation, and autophagy induction - making it a promising natural candidate for hyperpigmentation treatment. Our integrated approach combining computational screening with experimental validation provides a robust framework for identifying multi-target depigmenting agents.