Abstract
BACKGROUND: Radiation-induced salivary gland injury is a common complication of radiotherapy for head and neck tumors. The traditional Chinese herbal compound Shengmai San (SMS) can regulate Qi-Yin deficiency, promote fluid secretion, and alleviate thirst. However, its therapeutic effects on radiation-induced salivary gland damage remain unexplored. PURPOSE: This study aimed to investigate the therapeutic efficacy of Shengmai San in irradiation-induced salivary gland injury, identify its active pharmaceutical components, and elucidate the underlying molecular mechanisms of radioprotection. MATERIAL AND METHODS: The natural drug components of Shengmai San were analyzed, and a murine model of irradiation-induced salivary gland injury was established. SMS extract was administered to irradiated mice, and the functional restoration of salivary glands was evaluated. Network pharmacology was employed to identify the active constituents of SMS, while molecular docking and protein-protein interaction analysis were used to screen key signaling pathways associated with glandular functional preservation. In vitro and in vivo experiments were conducted to validate these findings. RESULTS: Shengmai San significantly alleviated irradiation-induced salivary gland injury by promoting M2 macrophage polarization and reducing the levels of Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) in serum and salivary gland tissues. It also ameliorated glandular fibrosis and inflammation. Network pharmacology analysis revealed that ophiopogonanone E was one of the primary active components, and molecular docking demonstrated its strong interaction with sphingosine kinase 1 (SPHK1) protein. In vivo experiments showed that SMS suppressed SPHK1 activity and sphingosine-1-phosphate (S1P) production in irradiated salivary glands. Additionally, SMS effectively inhibited the downstream receptor S1PR1. In vitro studies confirmed that SMS attenuated mitochondrial damage in acinar cells by inhibiting the SPHK1-S1P-S1PR1 axis and reduced glandular inflammation and oxidative stress by suppressing Nucleotide-binding Oligomerization Domain-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation, thereby preserving salivary gland function. CONCLUSION: Shengmai San effectively attenuates irradiation-induced salivary gland hypofunction and fibrosis, mainly through inhibition of the SPHK1-S1P-S1PR1 signaling pathway.