TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions

Despite the high incidence of dry mouth in postmenopausal women, its underlying mechanisms and therapeutic interventions remain underexplored. Using ovariectomized (OVX) mouse models, here this study identifies ferroptosis, an iron‐dependent regulated cell death, as a central mechanism driving postmenopausal salivary gland (SG) dysfunction. In the OVX‐SGs, TGFβ signaling pathway is enhanced with the aberrant TGFβ2 expression in SG mesenchymal cells. Intriguingly, TGFβ2 treatment reduces iron‐storing ferritin levels, leading to lipid peroxidation and ferroptotic death in SG epithelial organoids (SGOs). Mechanistically, TGFβ2 promotes the autophagy‐mediated ferritin degradation, so‐called ferritinophagy. A notable overexpression of the type III TGFβ receptor (TβRIII) is found in the OVX‐SGs and TGFβ2‐treated SGOs, while the silencing of TβRIII mitigates the ferroptosis‐mediated deleterious effects of TGFβ2 on SGOs. Finally, administration of ferroptosis inhibitor, Liproxstatin‐1 (Lip‐1), improves saliva secretion in OVX mice. Present findings collectively suggest a link between TGFβ signaling, ferroptosis, and SG injury, offering new therapeutic avenues for postmenopausal xerostomia. Ferroptosis is identified as a key mechanism in postmenopausal salivary gland dysfunction using ovariectomized (OVX) mouse models. Enhanced TGFβ signaling via TGFβ2‐TβRIII axis triggers ferritin degradation and lipid peroxidation, leading to ferroptosis in SG epithelial organoids. Administration of the ferroptosis inhibitor Liproxstatin‐1 (Lip‐1) restores SG function in OVX mice, unveiling promising therapeutic avenues for postmenopausal xerostomia.