Polygonatum sibiricum Alleviates Salivary Gland Dysfunction in Sjögren's Syndrome via CHRM3/AQP5 Axis Potentiation

Hydroxychloroquine (HCQ), a commonly used drug for Sjögren's syndrome (SS), is ineffective, highlighting the need for better treatments for salivary gland damage in SS. The study evaluated the effects of Polygonatum sibiricum (HJ) on SS using non-obese diabetic (NOD) mice treated with HJ, HCQ, or both for six weeks. Body weight, saliva levels, and submandibular gland histology were assessed. Various techniques were used to analyze apoptosis and oxidative stress. Network pharmacology identified therapeutic targets, and lentivirus technology was used to suppress CHRM3 gene expression to understand HJ's mechanisms against SS. HJ treatment significantly mitigates salivary gland damage, resulting in increased body weight, reduced water intake, and improved saliva flow rates. Histological evaluations revealed HJ reduced lymphocytic infiltration, restored glandular architecture, and alleviated oxidative stress. In addition, the study has the following key mechanistic finding: HJ upregulated the expression of the target proteins CHRM3 and AQP5 in submandibular glands. Additionally, HJ can significantly enhance the expression of CHRM3 and AQP5 in human salivary gland (HSG) cells after silencing CHRM3. This study revealed that HJ may act as a novel SS treatment by activating the CHRM3/AQP5 axis, promoting water channel transport, alleviating salivary gland damage, and enhancing saliva secretion. Moreover, the combination of HJ and HCQ could significantly improve the therapeutic benefit. These findings provide a new therapeutic strategy for SS.