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

• Published in: Inflammation research Vol. 74; no. 1; p. 84
• Main Authors: Weng, Xiuhong, Wang, Simin, Wang, Qing, Wei, Mingbo, Cheng, Bo
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2025; Springer Nature B.V
• Subjects: Allergology; Animal models; Animals; Autoimmune diseases; Biomedical and Life Sciences; Biomedicine; Dermatology; Epithelial cells; Epithelial Cells - drug effects; Epithelium; Exocrine glands; Female; Ferroptosis; Ferroptosis - drug effects; Glutathione; Glutathione peroxidase; Heme oxygenase (decyclizing); Heme Oxygenase-1 - metabolism; Humans; Immunology; Interferon-gamma - pharmacology; Melatonin; Melatonin - pharmacology; Melatonin - therapeutic use; Membrane Proteins; Mice; Mice, Inbred ICR; Mice, Inbred NOD; Neurology; NF-E2-Related Factor 2 - metabolism; NF-κB protein; Peroxidase; Pharmacology/Toxicology; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Rheumatology; Saliva; Salivary gland; Salivary glands; Salivary Glands - cytology; Salivary Glands - drug effects; Salivary Glands - pathology; Signal transduction; Signal Transduction - drug effects; Sjogren's syndrome; Sjogren's Syndrome - drug therapy; Sjogren's Syndrome - metabolism; Sjogren's Syndrome - pathology; Xerostomia; γ-Interferon; Ferroptosis; Melatonin; Salivary gland epithelial cells; Primary Sjögren’s syndrome
• ISSN: 1023-3830; 1420-908X; 1420-908X
• DOI: 10.1007/s00011-025-02047-y

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.