Minoxidil Sulfate Regulates JAK/STAT Signalling and Mitochondrial Function in Alopecia Areata.

Alopecia areata (AA) is an autoimmune hair disorder characterized by interferon-gamma (IFN-γ)-driven inflammation and collapse of hair follicle immune privilege. Although Janus kinase (JAK) inhibitors are effective, incomplete or delayed responses remain common. Minoxidil is frequently combined with JAK inhibitors in clinical practice, yet its immunomodulatory mechanisms in AA are unclear. We investigated the effects of minoxidil sulfate (MXS) on inflammatory signalling, immune privilege-associated features and mitochondrial stress responses, and evaluated whether MXS enhances the anti-inflammatory effects of the JAK inhibitor baricitinib. Clinical observations of patients receiving combination therapy were descriptively assessed. Mechanistic studies were conducted in human outer root sheath (ORS) cells stimulated with IFN-γ and polyinosinic:polycytidylic acid to model the AA inflammatory microenvironment. Representative clinical observations suggested accelerated hair regrowth after addition of oral minoxidil to baricitinib. In inflamed ORS cells, MXS enhanced baricitinib-mediated suppression of STAT1 phosphorylation and IFN-γ-inducible chemokines (CXCL9, CXCL10, CXCL11). MXS also exerted baricitinib-independent anti-inflammatory effects by inhibiting STAT1 and STAT3 activation. Furthermore, MXS reduced inflammatory induction of MHC class I expression and partially restored insulin-like growth factor-1 expression. MXS attenuated cytosolic and mitochondrial reactive oxygen species accumulation, mitochondrial DNA damage and loss of mitochondrial membrane potential, accompanied by suppression of NOX1 and NOX4 expression. These findings suggest that MXS modulates inflammatory signalling, preserves immune privilege-associated features and protects mitochondrial integrity, providing a mechanistic rationale for adjunctive use with JAK inhibitors without additional systemic immunosuppression.