Shatai Heji Mitigates Sjögren Disease-Induced Xerostomia by Regulating AQP5, NF-κB, and p38 MAPK Signaling Pathwaysaff

Fangbin Liu,* Jiyuan Chen,* Chunai Gong,* Minyan Chen, Gang Yang, Chun Chen, Ru Yao, Shengnan Li, Rong Wang, Yongfang Yuan Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rong Wang, Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, 280 Mohe Road, Shanghai, 201999, People’s Republic of China, Tel/Fax +86-021-56786907, Email [email protected] Yongfang Yuan, Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, 280 Mohe Road, Shanghai, 201999, People’s Republic of China, Tel/Fax +86-021-56786907, Email [email protected]: Xerostomia, commonly caused by Sjögren disease (SjD) or head and neck radiotherapy, significantly impairs patients’ quality of life, yet effective treatments remain limited. Traditional Chinese Medicine (TCM) offers promising alternatives due to its favourable efficacy and low toxicity. Shatai Heji (STHJ), a compound TCM formulation designed to nourish yin and invigorate qi, shows therapeutic potential for xerostomia. This study aimed to establish quality control standards for STHJ and evaluate its pharmacodynamics, safety, and mechanisms of action in models of xerostomia.Methods: A qualitative identification method was developed for the twelve herbal components of STHJ, with quantification of active constituents, focusing on quality markers for Astragalus and Rehmannia. Xerostomia was induced in Sprague–Dawley (SD) rats using a muscarinic receptor antagonist, and in BALB/c mice with SjD. Histological examination of major organs and salivary glands was performed, and aquaporin-5 (AQP5) expression in submandibular glands was assessed via Western blotting and immunohistochemistry. Therapeutic effects were evaluated through salivary secretion, glandular weight, and biochemical markers. In SjD mice, submandibular gland immunofluorescence and ELISA were used to assess inflammatory cytokines (TNF-α, TNF-β, IFN-γ, IL-6) and autoantibodies (anti-SSA/Ro, anti-SSB/La). Western blotting was used to analyse NF-κB and MAPK p38 pathway activation. Acute toxicity was assessed in SD rats.Results: STHJ significantly improved xerostomia symptoms, increased salivary output, upregulated AQP5, and preserved glandular morphology. It reduced fibrosis, suppressed inflammatory cytokine expression, and inhibited immune cell infiltration. Mechanistically, STHJ attenuated activation of NF-κB and MAPK p38 pathways. No acute toxicity was observed.Conclusion: This is the first study to establish quality control standards for STHJ and to demonstrate its anti-inflammatory and immunomodulatory effects in xerostomia models. The findings suggest that STHJ may serve as a safe and effective therapeutic option for xerostomia associated with SjD and other conditions. Keywords: shatai heji, STHJ, xerostomia, sjögren disease, SjD, submandibular glands, anti-inflammatory, AQP5