Huoxiang Zhengqi Alleviates Colitis-associated Cancer By Regulating Nrf2/NF-κB/NLRP3 Signaling

Colitis-associated cancer(CAC)is a subtype of inflammatory bowel disease(IBD)-associated colorectal cancer.With the continuous growth of CAC patients,CAC has attracted the widespread attention of many researchers,and we have found through experiments that the occurrence and development of CAC is closely related to inflammation and oxidative stress,and the interaction between pro-inflammatory cytokines and oxidative stress markers aggravates intestinal inflammation and further leads to tumor occurrence and growth,so it plays a key role in the progression of CAC.Although there are drugs on the market to relieve CAC,but its multiple side effects are not very suitable for specific groups of people and drug tolerance patients,and the therapeutic effect is limited,so we chose the classic Chinese herbal medicine Huoxiang Zhengqi(HXZQ),which is effective for gastrointestinal diseases,which is made of a variety of natural and safe Chinese herbal medicines,which has been used to treat intestinal diseases,however,anti-CAC effects and underlying mechanisms of HXZQ have not been reported.We confirmed the anti-CAC effect of HXZQ on azoxymethane oxide(AOM)/dextran sulfate sodium(DSS)-induced CAC mouse Model by performing relevant pharmacological experiments on HXZQ.Intestinal microbiota and serum metabolomics analyses indicated that HXZQ decreased the abundance of Candidatus Arthromitus,Turicibacter,Dorea,Acinetobacter,Clostridium,and Desulfovibrio and increased the abundance of butyric acid-producing bacteria,including Anaerotruncus,Prevotella,Butyricimonas,Bacteroides,Butyricicoccus,and Rikenella at the genus level.HXZQ altered the abundance of 29 serum metabolites in CAC mice.HXZQ significantly reduced colonic inflammation,suppressed the size and number of tumors,and reduced the levels of pro-inflammatory cytokines(interleukin [IL]-1α,IL1β,IL-6,IL-17 A,IL-21,IL-23),tumor necrosis factor-α(TNF-α),granulocyte macrophage-colony stimulating factor(GM-CSF),and oxidative stress markers(reactive oxygen species(ROS)and malondialdehyde(MDA)),and increased the levels of antiinflammatory cytokines(IL-27 and IL-10)in CAC mice.Additionally,HXZQ activated the nuclear factorerythroid factor 2-related factor 2(Nrf 2)signaling pathway and increased the levels of antioxidants such as catalase(CAT),superoxide dismutase-1(SOD-1),heme oxygenase-1(HO1),and NAD(P)H quinone oxidoreductases-1(NQO-1).HXZQ inhibited the activation of the nuclear factor kappa-B(NF-κB)signaling pathway and decreased the expression of NLR family pyrin domain containing 3(NLRP3)by inhibiting the phosphorylation of inhibitor of nuclear factor kappaB(IκB),inhibitor of nuclear factor kappa-B kinase(IKK),and NF-κB.In conclusion,HXZQ alleviated CAC in mice by modulating the intestinal microbiota and metabolism,activating Nrf 2-mediated antioxidant response,and inhibiting NF-κB-mediated NLRP3 inflammasome activation against inflammation.The present data provide a reference for the use of HXZQ as a therapeutic or combination agent for clinical CAC treatment.