Sjögren’s disease (SjD), a systemic autoimmune disease, is characterized by exocrine glandular damage and hypofunction. The molecular mechanism of SjD was still unknown. Mendelian analysis was conducted to identify the targets. Clinical characteristics of the serum protein were assessed in a cohort of SjD patients. In NOD mice, the target inhibitor was used to regulate lymphocytic infiltration and salivary secretion, and RNA-seq was conducted. Ferroptosis-related characters and salivary glandular function were evaluated in target-treated animals, as assessed by Fer-1 rescue. As the results indicated, Mendelian analysis identified LGALS9 (the gene encoding Gal9) as a key gene for SjD. In patients, clustering of CRP, ESR, IgG, and RF distinguished two patient groups with distinct Gal9 levels. Elevated Gal9 levels correlated with decreased unstimulated whole saliva flow and higher focus scores. GSE datasets showed that Gal9 is associated with the ferroptosis markers. In the NOD model, Gal9 inhibition reduced FS and IgG levels as well as decreased Th1 and Th17 infiltration. RNA-seq revealed enrichment of ferroptosis-related pathways in SjD. As a regulator of glutathione metabolism, Gal9 promotes ferroptosis through IFN-γ–dependent regulation of ACSL4 and GPX4. Meanwhile, the exacerbation of glandular injury and lipid peroxidation induced by Gal9 was abolished by ferroptosis inhibitor Fer-1. In conclusion, Gal9 promoted ferroptosis-related salivary gland dysfunction in SjD. Galectin9 (Gal9) acts as a pathogenic mediator in Sjögren’s disease (SjD) and a mechanistic amplifier of ferroptosis. Gal9 identified as an upstream inducer of ferroptosis, exacerbated the lymphocytic infiltration and glandular dysfunction in SjD. Inhibition of ferroptosis can restore Gal9-induced salivary gland dysregulation.
Liu et al. (2026) studied this question.