Ferroptosis in salivary gland disorders: mechanisms, biomarkers, and therapeutic perspectives

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been increasingly recognized as a key mechanism in salivary gland disorders. Initially identified in postmenopausal xerostomia, evidence now extends to autoimmune diseases, radiation-induced injury, hormonal regulation, and malignant tumors such as adenoid cystic carcinoma. Rather than being a secondary consequence of oxidative stress, ferroptosis actively contributes to epithelial damage, inflammatory amplification, and resistance to therapy. In Sjögren’s disease, interferon-γ promotes ferroptotic death of salivary epithelial cells through suppression of antioxidant defenses. Radiation accelerates ferritinophagy, iron release, and GPX4 loss, driving acinar injury that can be alleviated by radioprotective agents. Estrogen deficiency enhances ferroptosis via altered iron handling and hormone receptor signaling, while pharmacological inhibitors and natural compounds restore salivary function in experimental models. In malignant salivary tumors, inhibition of NOTCH1 or the use of iron-based nanomedicine induces ferroptosis and overcomes apoptosis resistance, highlighting its therapeutic promise. Beyond treatment, saliva and exosomal cargo have emerged as non-invasive sources of ferroptosis-related biomarkers, offering opportunities for disease monitoring and patient stratification. Despite these advances, challenges remain in validating biomarkers, characterizing alternative defense systems, and translating preclinical insights into clinical trials. Collectively, current findings position ferroptosis as both a mechanistic driver and a tractable therapeutic target in salivary gland biology, with broad implications for precision medicine.