Shi Pi Shu Gan Formula Prevents and Treats Sequelae of Pelvic Inflammatory Disease by Regulating PKA-CREB-Yap1 Signaling through the mtDNA/cGAS/STING Network.

OBJECTIVE: To investigate the effects and mechanisms of Shi Pi Shu Gan formula (SPSGF) on sequelae of pelvic inflammatory disease (SPID) in rats with liver stagnation and spleen deficiency. METHODS: A SPID rat model was established using mixed bacterial infection, mechanical injury, and compound stress (restraint, fatigue, diet disorder). Rats were divided into control, model, SPSGF-low (9.9 g/kg), SPSGF-high (36.9 g/kg), positive control, mitophagy inhibitor (Mdivi-1), SPSGF, and SPSGF+Mdivi-1 groups (n=6 each) for a 2-week treatment. Behavior, uterine histopathology (HE, TUNEL, immunohistochemistry), inflammatory cytokines (ELISA), mitophagy (TEM), and cGAS, STING, p-CREB, and p-YAP1 proteins (Western blot) were assessed. RESULTS: SPSGF treatment reduced inflammatory lesions and apoptosis in uterine tissue, decreased mtDNA levels and cGAS/STING expression, and increased p-CREB and p-YAP1 expression compared with the model group. DISCUSSION: This study's findings illuminate a novel link between mitochondrial quality control and tissue repair in SPID. Notwithstanding its limitations, including the model's translational capacity and the formula's complexity, this work lays the groundwork for developing SPSGF as a promising multi-targeted therapeutic strategy, aligning with TCM principles for managing chronic inflammatory sequelae. CONCLUSION: SPSGF may inhibit the inflammatory response in SPID rats by activating mitophagy to inhibit excessive activation of the cGAS/STING pathway and by activating the downstream PKACREB- Yap1 signaling pathway by interfering with the mtDNA-cGAS-STING network, thereby alleviating the symptoms of SPID.