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

<b>Background/Objectives:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> 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.