2. Academic Validation
  3. Salidroside Selectively Binds to SEC23A and Ameliorates Psychological Stress-Induced Hyperpigmentation

Salidroside Selectively Binds to SEC23A and Ameliorates Psychological Stress-Induced Hyperpigmentation

  • Pharmaceuticals (Basel). 2026 Mar 16;19(3):487. doi: 10.3390/ph19030487.
Man Yang 1,  Xiaoyu Sun 1,  Da Wang 1,  Huizhong Nie 1,  Kang Cheng 2,  Jie Gu 2,  Lu Chen 3,  Yuxuan Zhang 4,  Lingli Yang 5,  Ichiro Katayama 5,  Yiming Li 1,  Huali Wu 1
Affiliations

Affiliations

  • 1 Department of TCM Chemistry, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 Shanghai Inoherb Cosmetics Co., Ltd., Shanghai 200080, China.
  • 3 Development and Planning Department, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 4 Pharmaceutical Research Laboratory, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai 200437, China.
  • 5 Department of Pigmentation Research and Therapeutics, Graduate School of Medicine, Osaka Metropolitan University, Osaka 530-0001, Japan.
PMID: 41901332 DOI: 10.3390/ph19030487
Abstract

Background/Objectives: Psychological stress triggers excessive melanin deposition via neuroendocrine pathways, yet targeted interventions for stress-induced hyperpigmentation remain limited. Salidroside (SAL) exhibits established depigmenting effects in UV-induced models and possesses neuroprotective properties. This study investigated SAL's efficacy in psychological stress-induced hyperpigmentation and elucidated its underlying mechanisms. Methods: B16F10 melanocytes, C57BL/6J mice, zebrafish, and human foreskin organ cultures were subjected to stress factor (Substance P/cortisol) or α-MSH/IBMX stimulation to model psychological stress-induced and canonical cAMP-driven hyperpigmentation, respectively. Melanin content, Tyrosinase activity, melanosome maturation (transmission electron microscopy/HMB45 staining), and melanogenic protein/mRNA expression were assessed. Drug Affinity Responsive Target Stability (DARTS) assays, molecular docking, and SEC23A siRNA knockdown were employed to identify and validate SAL's molecular target and downstream signaling pathways. Results: SAL dose-dependently reduced melanin content, Tyrosinase activity, and TYR/TRP-1/DCT expression in SP/Cort-stimulated melanocytes, exhibiting greater potency (200 μM) than in IBMX-induced models (400 μM). SAL reversed SP/Cort-induced hyperpigmentation in human skin explants, zebrafish, and C57BL/6J mice, and normalized melanosome number/maturation. DARTS and molecular docking identified SEC23A as a direct SAL-binding target. SP/Cort specifically upregulated SEC23A, which SAL suppressed. SAL concurrently activated the SEC23A-p-ERK-MITF axis and inhibited the NK1R-p38-MITF axis in the stress model. SEC23A knockdown potentiated SAL's anti-melanogenic effects specifically in SP/Cort-stimulated cells. Conversely, in IBMX-induced models, SEC23A remained unchanged, and SAL acted via PKA/CREB, PI3K/Akt, and Wnt/β-catenin pathways. Conclusions: SEC23A is a novel core target in psychological stress-induced hyperpigmentation. SAL selectively binds SEC23A to inhibit stress-induced melanogenesis via dual ERK and p38 MAPK signaling axes, demonstrating etiological specificity distinct from canonical cAMP pathway inhibition.

Keywords

SAL; SEC23A; hyperpigmentation; melanin; psychological stress.

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