6-Gingerol and 6-shogaol attenuate chemotherapy-induced nausea and vomiting via ameliorating mitochondrial dysfunction and pyroptosis through JNK/MFF signaling pathway

Abstract

6-Gingerol and 6-shogaol, the main active compounds in ginger, have been proven to have antiemetic effect, and can be employed to alleviated chemotherapy-induced nausea and vomiting (CINV), but the underlying mechanisms remain unclear. We aimed to investigate whether 6-gingerol and 6-shogaol attenuate CINV through ameliorating mitochondrial dysfunction and pyroptosis-induced gastrointestinal inflammation injuries. Cisplatin-induced pica rat model was established to investigate the antiemetic effects of 6-gingerol (100 mg/kg) and 6-shogaol (100 mg/kg) against CINV. Cisplatin-stimulated IEC-6 cell inflammation injury model was established to further explore the protective mechanisms. The antiemetic efficacy was observed by kaolin intake (a pica response analogous to nausea and vomiting). Here, in vivo, 6-gingerol and 6-shogaol significantly reduced the kaolin intake, alleviated gastrointestinal injury, and decreased the levels of inflammatory cytokines (IL-1β, TNF-α) in pica rats. Moreover, 6-gingerol and 6-shogaol reduced mitochondrial damage, modulated disturbed mitochondrial dynamics, and inhibited GSDME-mediated pyroptosis. In vitro, 6-gingerol and 6-shogaol significantly restored mitochondrial membrane potential and morphology. Mechanistically, we found that 6-gingerol and 6-shogaol blocked the JNK/MFF signaling pathway, which attenuated mitochondrial dysfunction and subsequently prevented GSDME-mediated pyroptosis. Collectively, this study suggested that 6-gingerol and 6-shogaol have antiemetic effects against CINV, which are associated with inhibiting mitochondrial dysfunction and GSDME-mediated pyroptosis via JNK/MFF pathway.