Salvianolic acid A enhances Treg accumulation via the RUNX1/CBFβ/FOXP3 axis as a neuroprotective immunomodulator in ischemic stroke

Salvianolic acid A (SAA), a major water-soluble bioactive compound extracted from Salvia miltiorrhiza, has been extensively studied for its diverse pharmacological properties in cerebrovascular diseases. However, its immunomodulatory effects on lymphocytes in stroke remain incompletely understood. This study systematically investigated the therapeutic efficacy and underlying mechanisms of SAA in a murine model of transient middle cerebral artery occlusion (tMCAO). Early administration of SAA (20 mg/kg) to ischemic stroke (IS) mice demonstrated neuroprotective effects, characterized by reduced infarct volume and improved behavioral outcomes, alongside creating a T_reg-favorable environment in the spleen. In T cells differentiation assays and a luciferase reporter gene system, SAA was further identified as the primary active component in Salvia miltiorrhiza extract responsible for promoting in vitro T_reg differentiation. Flow cytometry analysis revealed that SAA treatment significantly enhanced the accumulation of T_reg cells in the brain after tMCAO, potentiated the immunosuppressive profile of the cerebral microenvironment, alleviated inflammatory responses, and avoided inducing systemic immunosuppression, ultimately leading to substantial neurological improvement. T_reg depletion abolished SAA-induced neuroprotection. Mechanistically, SAA appeared to regulate T_reg differentiation through the RUNX1/CBFβ/FOXP3 axis independent of TGF-β signaling. In summary, these findings suggest that SAA improved stroke outcomes via upregulation of cerebral Treg cells abundance, a process linked to the RUNX1/CBFβ/FOXP3 pathway. Collectively, this study offers new perspectives on the therapeutic potential of SAA in ischemic stroke management.

Immunomodulator; Ischemic stroke; RUNX1/CBFβ complex; Salvianolic acid A; Treg cells.