<p>Sjögren’s syndrome (SS) is a chronic autoimmune disease in which inflammatory cells infiltrate the exocrine glands, reducing glandular secretory function and ultimately resulting in keratoconjunctivitis sicca (dry eyes) and xerostomia (oral dryness). Cardiovascular risk factors are more prevalent in patients with SS than in healthy controls; patients with SS and metabolic syndrome also have higher leptin and inflammatory cytokine levels. In this study, we investigated the effects of HGR4113, a structural analogue of glabridin that promotes mitochondrial function and is in clinical trials for obesity treatment, on the development of SS in non-obese diabetic NOD/ShiLtJ mice. HGR4113 inhibited IL-17 production by regulating STAT3 activity and the metabolic profile of splenic CD4⁺ T cells; it also increased the frequency of IL-10-producing regulatory B cells and decreased immunoglobulin production. Oral administration of HGR4113 (100 mg/kg) improved salivary flow rate, reduced lymphocyte infiltration and lowered inflammatory cytokine levels in the salivary glands of NOD/ShiLtJ mice. HGR4113 also decreased the frequencies of splenic IL-17-producing T and B cells, germinal-centre B cells and plasma cells ex vivo in NOD/ShiLtJ mice. Additionally, 3D epithelial structure formation from salivary gland cells of HGR4113-treated NOD/ShiLtJ mice increased, as did the levels of E-cadherin, aquaporin-5, α-SMA and cytokeratin-14. Finally, treatment with HGR4113 promoted the development of 3D salivary epithelial structures in vitro. HGR4113 improves salivary gland hypofunction by inhibiting lymphocyte infiltration and inflammation in the salivary glands and restoring damaged salivary tissue in SS-like NOD/ShiLtJ mice.</p><p></p>