Maidong Dishao Decoction can inhibit the activation of the cGAS-STING signaling pathway of Sjögren's syndrome by reducing oxidative stress in salivary gland epithelial cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Sjögren's syndrome (SS) is an autoimmune disorder primarily characterized by the involvement of exocrine glands. Currently, effective interventions need to be explored to preserve glandular function. Maidong Dishao Decoction (MDDST), which has been widely used in the treatment of Sjögren's syndrome for over 20 years, functions to nourish yin and promote fluid production, as well as to regulate lung qi to distribute body fluids-particularly benefiting patients with yin and fluid deficiency. However, its exact pharmacological mechanism remains unclear.

AIM OF THE STUDY: This study aimed to investigate the underlying mechanism of MDDST in the treatment of Sjögren's syndrome.

MATERIALS AND METHODS: First, the UHPLC-QE-MS analysis was used to identify the key components of MDDST drug-containing serum. The study selected female non-obese diabetic (NOD) mice and ICR mice, which were intragastrically administered with varying doses of MDDST or normal saline daily for 8 weeks. The effect of MDDST on NOD mice was assessed by water intake volume, histopathological analysis, and serum level of IgG and SSA. Transcriptome sequencing was performed to investigate the molecular mechanisms and potential targets of MDDST in the SS. The protein expression levels of the relevant pathways were assessed using Western blot, immunohistochemistry, and immunofluorescence techniques. Finally, in vitro experiments were performed to investigate the specific action mechanism of MDDST.

RESULTS: MDDST treatment for 8 weeks significantly improved the disease state of NOD mice. Transcriptome sequencing results suggested that the oxidative phosphorylation signaling pathway was significantly changed after the intervention of MDDST. Furthermore, MDDST can inhibit excess ROS accumulation and maintain mitochondrial membrane potential in the submandibular gland epithelial cells of NOD mice. Moreover, it can also suppress the key protein expression of the cGAS-STING signaling pathway and mitophagy signaling pathway. However, the autophagy inhibitor 3 MA can partially reverse the therapeutic effect of MDDST in NOD mice. Through in vitro experiments, we further discovered that the application of the 3 MA could reverse the therapeutic effect of MDDST-containing serum, thereby enhancing the activation of ROS and the cGAS-STING signaling pathway in A253 cells. Conversely, the use of NAC to inhibit ROS production not only suppressed the cGAS-STING signaling pathway but also attenuated maladaptive autophagy induced by H2O2, thus mimicking the therapeutic effects of MDDST-containing serum.

CONCLUSIONS: Maidong Dishao Decoction alleviates the activation of the cGAS-STING signaling pathway and maladaptive mitophagy in Sjögren's syndrome by suppressing ROS production and preserving mitochondrial homeostasis in Salivary gland epithelial cells (SGECs).