biostudies-literatureUnknown15(1)Deng RSkin 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 upregScientific reports30689https://www.ebi.ac.uk/biostudies/studies/S-EPMC12371102biostudies-literatureNatural dual inhibitor isorhamnetin-3-O-neohespeidoside targets tyrosinase and MC1R for skin pigmentation management.PMC12371102Deng RShen ZOu ZHuang GZheng SXie SfalseNatural dual inhibitor isorhamnetin-3-O-neohespeidoside targets tyrosinase and MC1R for skin pigmentation management.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 upreg2025-01-01T00:00:00Z2025 Aug2026-07-15T05:58:15.364Z2026-06-30T03:16:17.08ZS-EPMC123711024084138510.1038/s41598-025-08485-2