Melatonin inhibits salivary gland epithelial cell ferroptosis via the NRF2/HO-1/GPX4 signaling pathway in primary Sjögren's syndrome

Background: Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by xerostomia and autoimmune sialadenitis. Interferon-γ (IFN-γ) induces Ferroptosis in salivary gland epithelial cells (SGECs), leading to salivary gland (SG) hypofunction. We previously demonstrated the beneficial effects of melatonin (MLT) in alleviating SG dysfunction and inflammation in a pSS animal model. However, the precise underlying mechanism remains unclear.

Methods: Female NOD/ltj and ICR mice were used as the pSS mouse model and control group, respectively. MLT was administered via intraperitoneal injection to NOD/ltj mice to detect its effect on Ferroptosis in SGs. Primary human SGECs and A253 cells were treated with IFN-γand Ferroptosis inducers, with or without MLT.

Results: Exogenous MLT alleviated pathological SG alterations and promoted saliva production through inhibiting SGEC Ferroptosis. MLT inhibited SGEC Ferroptosis induced by IFN-γ and Ferroptosis inducers via nuclear factor erythroid 2-related factor 2/heme oxygenase-1/Glutathione Peroxidase 4 (NRF2/HO-1/GPX4) pathway activation. Moreover, MLT suppressed the nuclear factor-kappa B (NF-κB) pathway, which is triggered by Ferroptosis in SGECs. Nevertheless, ML385-mediated NRF2 inhibition abrogated the antiferroptotic protective effects of MLT on SGECs.

Conclusions: MLT inhibits SGEC Ferroptosis through NRF2/HO-1/GPX4 pathway activation and thus attenuates ferroptosis-triggered NF-κB activity. Melatonin represents a potential therapeutic approach for pSS owing to its capacity to regulate Ferroptosis.

Ferroptosis; Melatonin; Primary Sjögren’s syndrome; Salivary gland epithelial cells.