Metformin Attenuates Partial Epithelial-Mesenchymal Transition in Salivary Gland Inflammation via PI3K/Akt/GSK3β/Snail Signaling Axis

Chronic inflammation in the salivary glands (SG) often triggers epithelial-mesenchymal transition (EMT), leading to the loss of acinar function and promoting fibrosis. This study explores the role of Metformin in mitigating partial EMT in SG inflammation. In vitro, human salivary gland epithelial cells (hSGECs) were treated with lipopolysaccharide (LPS) and Metformin. EMT markers and the PI3K/Akt/GSK3 beta/Snail signaling axis were assessed using RNA-seq and Western blot analysis. In vivo, a Wharton's duct ligation rat model was employed to mimic chronic sialadenitis (CS). Nine Wistar rats were randomly divided into three groups: Control, Ligation and Ligation + Metformin groups, with three rats per group. After ductal ligation, the Ligation + Metformin group received 100 mg/kg of Metformin via intragastric administration, while the Control and Ligation groups received an equivalent saline every 24 h. Histological analysis, immunohistochemical and immunofluorescence staining were conducted to evaluate acinar morphology, EMT, and the PI3K/Akt/GSK3 beta/Snail signaling axis. The results showed that in CS tissues, atrophied acinar cells underwent partial EMT. In vitro, Metformin reversed LPS-induced EMT in hSGECs. RNA-seq and Western blot revealed that Metformin achieved this effect by targeting the PI3K/Akt/GSK3 beta/Snail signaling axis (P < 0.01). In ductal ligation models, Metformin treatment restored ligation-induced acinar damage and functional loss (P < 0.01). Further histological evidence supported that Metformin mitigated EMT by inhibiting inflammatory activation of PI3K/Akt/GSK3 beta/Snail signaling axis (P < 0.01). In conclusion, Metformin alleviates partial EMT in SG inflammation by targeting the PI3K/Akt/GSK3 beta/Snail signaling axis, highlighting its potential as a therapeutic strategy for SG inflammation.