Diarylheptanoid Phytoestrogen from Curcuma comosa Attenuates Colitis and Colitis-Associated Colorectal Cancer by Inhibiting Inflammation and Oxidative Stress and Modulating Gut Microbiota

Diarylheptanoids are bioactive compounds primarily found in the rhizomes of Curcuma species and are traditionally used to treat inflammatory conditions. This study investigated the chemopreventive effects of 1,7-diphenyl-(4E, 6E)-4,6-heptadien-3-one (DPH), a diarylheptanoid isolated from Curcuma comosa ethanol extract (CCE), using in vitro and in vivo models. CCE/DPH administration significantly alleviated colitis and delayed colitis-associated colorectal tumorigenesis, accompanied by reduced expression of proinflammatory cytokines and mediators. Network pharmacology and experimental validation suggested potential involvement of the Toll-like receptor 4/mitogen-activated protein kinase/nuclear factor kappa B/signal transducer and activator of transcription 3 axis as a potential therapeutic target. Additionally, CCE/DPH upregulated the expression of the phase II antioxidant enzymes and tight junction proteins. Microbiome analysis revealed that CCE/DPH was associated with partial improvements in the gut microbial composition and metabolite profiles in experimental models. Overall, these findings support the preventive potential of CCE and DPH against experimental colitis and colitis-associated colorectal cancer.