Targeting Ferroptosis to Restore Salivary Gland Homeostasis in an Obesity Model

Obesity is a systemic metabolic disorder that is known to impair various organ systems; however, its precise impact on salivary gland homeostasis remains unclear. Recent studies have implicated ferroptosis—an iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative stress—in glandular dysfunction. In this study, we used leptin-deficient (ob/ob) mice to elucidate the role of ferroptosis in obesity-associated salivary gland pathology. The protective effects of ferroptosis in-hibition were evaluated by administering ferrostatin-1 (a lipid reactive oxygen species [ROS] scavenger) and deferoxamine (an iron chelator) for an 8-week period. Obese mice exhibited significantly increased body weight, food intake, and hyperglycemia. These systemic changes are accompanied by profound histological alterations in the salivary glands, including lipid droplet ac-cumulation, acinar atrophy, and mitochondrial ultrastructural damage. These alterations correlate with the hallmarks of ferrop-totic injury, including increased ROS levels, elevated malondialdehyde levels, suppressed glutathione peroxidase 4 activity, and iron overload. Salivary gland fibrosis, inflammation, and secretory dysfunction were evident, characterized by the upregulation of TGF-β and Collagen I, reduced expression of aquaporin-5 and amylase, and dysregulated levels of autophagy-related markers (LC3B and p62). Treatment with either ferrostatin-1 or deferoxamine significantly mitigated these pathologies; however, the degree of efficacy varied depending on the specific parameters that were examined. Thus, our findings implicate ferroptosis is a critical contributor to salivary gland dysfunction in obesity, and suggest that pharmacological inhibition of this pathway repre-sents a viable therapeutic strategy for preserving glandular integrity under metabolic stress.