MaiMenDong Decoction Alleviates Primary Sjögren's Syndrome by Dual Suppression of Inflammation and Immune Dysregulation: A Synergy of Network Pharmacology and NOD/Ltj Mouse Studies.

INTRODUCTION

To investigate the potential efficacy and molecular mechanisms of MaiMenDong Decoction (MMDT) and its split formula for the treatment of primary Sjögren's Syndrome (pSS), focusing on the TLR4/MyD88/NF-κB signaling pathway and immunomodulation.

METHODS

We combined network pharmacology with screening to identify the active ingredients and targets of MMDT and constructed an "ingredient-target-disease" network. In the NOD/Ltj mouse model, MMDT, Maidong, Maidong-Gancao, hydroxychloroquine (HCQ), and the NF-κB inhibitor Pyrrolidine Dithiocarbamate ammonium salt (PDTC) were administered for 8 weeks to systematically evaluate salivary secretion, immune function, and pathological changes of the submandibular gland. Treg cell differentiation was detected by flow cytometry. TLR4/MyD88/NF-κB pathway activity and AQP5 expression were detected by immunohistochemistry, qPCR, and Western blot, and hepatic energy metabolism-related enzyme activities were analyzed.

RESULTS

Network pharmacology analysis revealed that the core active components of MMDT synergistically modulated inflammation-associated pathways. Animal experiments demonstrated that MMDT significantly improved salivary secretion function in pSS model mice, alleviated lymphocyte infiltration in submandibular glands, and positively regulated splenic Treg cell differentiation. At the molecular level, MMDT and its split formula suppressed the TLR4/MyD88/NF-κB signaling pathway, upregulated AQP5 levels in submandibular glands, and exerted regulatory effects on hepatic energy metabolism abnormalities.

CONCLUSION

MMDT exerts its therapeutic effects on pSS through multi-target inhibition of TLR4/MyD88/NF-κB pathway activation, thereby reducing the release of pro-inflammatory cytokines, promoting Treg cell-mediated restoration of immune homeostasis, and recovering AQP5- dependent salivary secretion function. These findings collectively provide novel mechanistic evidence for the application of Traditional Chinese Medicine (TCM) in the treatment of pSS. </p>.