6-Shogaol attenuates cisplatin induced emesis by inhibiting the mtDNA-cGAS-STING signaling pathway in a rat pica model

Ethnopharmacological relevance: Ginger (Zingiber officinale Rosc.) is a traditional anti-emetic herb. 6-shogaol, the main active compound of ginger, is reported to possess a variety of bioactivities. Aims of the study: This study aimed to investigate the anti-emetic effect of 6-shogaol in a cisplatin-induced pica rat model and explore its underlying mechanism. Materials and methods: The rat pica model was established by intraperitoneal injection of cisplatin. The pathological damage of gastric antrum and ileum were observed by hematoxylin-eosin staining. The levels of serum 8Hydroxy-desoxyguanosine (8-OHdG) were detected by ELISA. The expression of ZO1 tight junction protein (TJP1) and occludin in ileum were determined by IHC. The levels of 8-oxo G DNA glycosylase 1 (OGG1), flap endonuclease 1 (FEN1), cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), phosphoSTING (p-STING), TANK binding kinase 1 (TBK1), phospho-TBK1 (pTBK1), nuclear factor kappa-B (NF-kappa B) and phospho-NF-kappa B (p-NF-kappa B) in gastric antrum and ileum were assayed by western blotting. Results: We found that 6-shogaol significantly improved pica behavior in rats by downregulating NF-kappa B and IL-1 beta level, and ameliorating inflammatory damage in gastric antrum and ileum. Mechanistically, cGAS-STING axis activated by mtDNA is responsible for the cisplatin-induced gastrointestinal inflammatory responses. 6-Shogaol inhibited the mtDNA-cGAS-STING signaling pathway by increasing the level of base-excision repair enzyme OGG1 and decreasing the level of endonuclease FEN1. Conclusions: This study indicates that 6-shogaol has a therapeutic effect against chemotherapy-induced nausea and vomiting (CINV), potentially attributable to the suppression of the mtDNA-cGAS-STING signaling pathway.