Oleanolic acid alleviates stress-induced alopecia via modulating brain-skin axis: Neuroprotection and dermal papilla cell senescence.

Psychological stress-induced alopecia is becoming increasingly prevalent in younger populations; however, effective nutritional interventions remain limited. To investigate the therapeutic effects and underlying mechanisms of the natural product component Oleanolic acid (OA) on stress-induced alopecia. A chronic unpredictable mild stress (CUMS)-induced C57BL/6 J mouse model was established to evaluate the efficacy and potential mechanisms of Oleanolic acid. Evaluation and molecular biology experiments were conducted using pathological staining, commercial assay kits, Western Blot (WB), and LC/MS. In vitro, corticosterone-induced injury models were established in HT22 cells and primary mouse dermal papilla cells. Confocal microscopy, flow cytometry, and WB were employed to explore the mechanisms of OA. Oral administration of OA significantly ameliorated anxiety-like behaviors and reversed the stagnation of hair growth in CUMS mice. Pharmacokinetic analysis confirmed the distribution of OA in both brain and skin tissues. Mechanistically, OA rebalanced neurotransmitter levels (reducing the 5-HIAA/5-HT and Glu/GABA ratios) and downregulated hypothalamic-pituitary-adrenal (HPA) axis hormones (corticosterone, cortisol). In the brain, OA attenuated neuronal degeneration and oxidative stress via the BDNF/CREB signaling pathway. In the skin, OA reduced inflammation and oxidative damage, promoted hair follicle regeneration, and increased skin thickness by activating the Wnt/β-catenin pathway and upregulating GAS6. Furthermore, in vitro studies demonstrated that OA mitigated corticosterone-induced ferroptosis-like changes (restoring SLC7A11 and GPX4 levels) in HT22 cells. In primary dermal papilla cells, OA inhibited stress-induced senescence and cell cycle arrest by modulating P53 and activating Wnt/β-catenin signaling. These findings suggest that OA effectively alleviates stress-induced alopecia by regulating the brain-skin axis, highlighting its potential as a functional food ingredient for stress management.