Targeting the ferritinophagy axis: multi-target regulation of TFRC/FTH1/NCOA4 by artesunate ameliorates salivary gland dysfunction in Sjögren's Disease

  • Chin Med. 2026 Mar 19;21(1):97. doi: 10.1186/s13020-026-01354-8.
Yong Luo  1  2 ,  Liuting Zeng  1  3  4 ,  Yaru Zheng  3 ,  Xiaomin Li  5 ,  Mingjuan Liu  4 ,  Ningyu Guo  6 ,  Genghong Yao  4 ,  Lingyun Sun  7  8  9
Affiliations
  • 1. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
  • 2. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
  • 3. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 4. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
  • 5. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China.
  • 6. College of Materials Science and Technology, Nanjing University of Aeronautics and Astronautics, Nanjing, China.
  • 7. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China. [email protected].
  • 8. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China. [email protected].
  • 9. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. [email protected].
PMID: 41851758 DOI: 10.1186/s13020-026-01354-8
Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords
Artesunate; Ferritinophagy; Ferroptosis; Single-cell transcriptomics; Sjögren’s Disease; TFRC/FTH1/NCOA4 axis.
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