Luteolin alleviates hyposalivation by upregulating AQP5 through binding to estrogen receptor beta and potentiating the saliva secretion signaling pathway.

Xerostomia, common in postmenopausal women, is highly prevalent and significantly diminishes quality of life. However, effective clinical treatments with minimal side effects are limited. This study aimed to investigate therapeutic effect of luteolin in menopausal xerostomia treatment and its potential underlying mechanisms. Luteolin upregulated aquaporin 5 (AQP5), a key regulator of saliva secretion. Luteolin has estrogen-like effects, which exhibits good binding capacity with estrogen receptor beta. In luteolin-induced submandibular gland cells, estrogen receptor beta overexpression (interference) upregulated (downregulated) AQP5 expression. The ChIP assay revealed that the luteolin/estrogen receptor beta complex binds to the estrogen response element of AQP5 promoter, upregulating AQP5 expression. Investigation of the therapeutic effects of luteolin using ovariectomized (OVX) mice as a model for menopausal xerostomia demonstrated that luteolin ameliorated OVX-induced hyposalivation in mice. High transcriptome sequencing of mice submandibular glands revealed a dysregulated saliva secretion signaling pathway in the OVX group compared with that in the control group. The salivary secretion signal in the luteolin group was upregulated relative to that in the OVX group. Adrenergic receptor alpha1a, adrenergic receptor beta1, salivary amylase 1 (Amy1), and Aqp5 were identified as saliva secretion signaling-related differentially expressed genes. The qPCR and immunohistochemical staining confirmed the reversal of the OVX-induced downregulation of adrenergic receptor alpha1a, adrenergic receptor beta1, Amy1 and Aqp5 by luteolin. Our results indicated that luteolin alleviates hyposalivation by upregulating AQP5 through binding to estrogen receptor beta and potentiating the saliva secretion signaling pathway. These results suggest a potential therapeutic application of luteolin for menopausal xerostomia treatment.