Background <p>Sjögren’s Disease (SJD) is an autoimmune disorder involving lymphocytic infiltration of exocrine glands, notably salivary and lacrimal glands, causing dysfunction. Ferroptosis, an iron-dependent cell death pathway, contributes to glandular injury. Ferritinophagy, regulated by the TFRC/FTH1/NCOA4 axis, releases iron and promotes ferroptosis. Effective therapeutic strategies targeting this axis are limited.</p> Objective <p>To investigate if artesunate (ART), an artemisinin derivative with anti-inflammatory/antioxidant properties, inhibits ferroptosis by modulating the TFRC/FTH1/NCOA4 axis and alleviates salivary gland dysfunction in SJD.</p> Methods <p>Non-Obese Diabetic (NOD) mice (SJD model) were orally treated with ART. IFN-γ induced ferroptosis in human salivary gland (A253) cells. Analyses included scRNA-seq, bulk RNA-seq, molecular docking, Western blotting, immunofluorescence, flow cytometry, and functional assays.</p> Results <p>ART significantly improved salivary gland histopathology and function in NOD mice, reducing inflammatory infiltration and increasing saliva flow. ART also lowered serum IgG and hepatic/renal dysfunction markers. Cellularly, ART suppressed IFN-γ-induced lipid peroxidation, mitochondrial damage, and rescued viability and aquaporin 5 (AQP5) expression. Mechanistically, ART modulated the TFRC/FTH1/NCOA4 axis: downregulating TFRC (iron uptake), upregulating FTH1 (iron storage), and reducing NCOA4 and LC3-II/I (suppressing ferritinophagy), ultimately downregulating heme iron levels. Docking indicated that ART binds the FTH1–NCOA4 interface, potentially hindering ferritin degradation. ART also upregulates GPX4 and xCT, synergistically inhibiting ferroptosis.</p> Conclusion <p>ART mitigates SJD-associated salivary gland dysfunction by dually targeting the ferritinophagy axis (TFRC/FTH1/NCOA4 modulation) and augmenting antioxidant defense, supporting novel therapeutics targeting ferroptosis for SJD.</p> Graphical Abstract <p></p>