Corticotropin-releasing hormone inhibits autophagy by suppressing PTEN to promote apoptosis in dermal papilla cells

Background: Stress-related hair loss is on the rise, largely due to escalating levels of stress-related corticotropin-releasing hormone (CRH) through poorly defined mechanisms. CRH-mediated activation of corticotropin-releasing hormone receptors (CRHRs) on dermal papilla cells (DPCs) is a likely cause of stress-related hair loss. The aim of the study is to elucidate the key mechanisms of alopecia caused by CRH and provide potential new targets for the treatment of stress-related hair loss.

Methods: 4D label-free quantitative proteomics of DPCs and the chronic unpredictable mild stress mouse (CUMS) model were used to explore the relationship and mechanism between CRH, DPCs and hair regeneration.

Results: CRH initially downregulated PTEN to suppress Autophagy, leading to DPC Apoptosis. Overexpression of PTEN enhanced Autophagy and mitigated CRH-dependent DPC Apoptosis. CRH inhibited PTEN and activated the PI3K/Akt/mTOR pathway, whereas rapamycin inhibited this pathway and activated Autophagy, consequently lowering Apoptosis, suggesting that increased susceptibility to Apoptosis is caused by decreased Autophagy. CUMS-induced hair growth disruption is accompanied by an increase in CRHRs and a decrease in PTEN levels within the dermal papilla. Intracutaneous injection of CRH impeded hair regeneration and decreased PTEN in mice, concurrent with inhibition of Autophagy and increased Apoptosis.

Conclusions: These findings indicate that PTEN loss coupled with PI3K/Akt/mTOR-mediated Autophagy inhibition and Apoptosis in DPCs is a key mechanism of stress-related hair loss induced by CRH and suggests that topical activation of PTEN or enhancement of Autophagy, e.g. through rapamycin, may have a therapeutic effect on stress-induced hair loss disorders such as alopecia.

Hair loss; PI3K/AKT/mTOR; chronic unpredictable mild stress; hair regrowth; hypothalamic–pituitary–adrenal axis.