Natural triterpenoid Ardisiacrispin B attenuates colitis-associated cancer via JAK2/STAT3 pathway and gut microbiota modulation

TL;DR

Ardisiacrispin B, a natural compound, reduces colon cancer linked to inflammation by balancing gut bacteria and blocking harmful signaling pathways.

Contribution

This study is the first to show Ardisiacrispin B's protective effects against colitis-associated cancer via gut microbiota modulation and JAK2/STAT3 pathway inhibition.

Findings

Ardisiacrispin B reduced disease severity and tumor burden in a mouse model of colitis-associated cancer.

The compound modulated gut microbiota and suppressed pro-inflammatory cytokines in the colon.

Ardisiacrispin B induced apoptosis in colonic epithelial cells and inhibited key oncogenic pathways like JAK2/STAT3.

Abstract

Colitis-associated cancer (CAC) arises from persistent intestinal inflammation, immune dysregulation, and microbiota-driven epithelial injury, representing a major link between inflammatory bowel disease and colorectal malignancy. Despite advances in therapy, colon cancer remains one of the leading causes of cancer-related mortality worldwide, underscoring the urgent need for effective preventive and immunomodulatory interventions. Ardisiacrispin B (AB), a bioactive triterpenoid isolated from the Ardisia genus, has been reported to suppress tumor growth by regulating apoptosis and ferroptosis; however, its role in inflammation-driven colorectal tumorigenesis remains unexplored. In this study, we investigated the protective and antitumor effects of AB in an azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CAC mouse model, with a focus on inflammatory signaling pathways, epithelial remodeling, and gut microbiota modulation. AB administration markedly alleviated disease severity, as evidenced by a significant reduction in disease activity index, including body weight loss, diarrhea, and rectal bleeding. Histopathological evaluation revealed preserved colonic mucosal architecture, diminished inflammatory cell infiltration, and a pronounced reduction in tumor number and size. AB treatment partially modulated the gut microbiota, with a trend toward enrichment of beneficial taxa and a reduction in inflammation-associated bacterial populations. Concurrently, AB robustly downregulated the colonic expression of pro-inflammatory cytokines and chemokines. AB treatment was associated with increased expression of pro-apoptotic markers, indicative of enhanced apoptotic signaling in colonic epithelial cells, as indicated by increased expression of cleaved PARP, cleaved caspase-3, p53, and BAX, while markedly inhibiting cellular proliferation through suppression of Ki-67. Mechanistically, AB was associated with attenuation of key inflammatory and oncogenic signaling pathways, including IL-6/JAK2/STAT3, LPS/TLR4/MyD88/NF-κB, and MAPK cascades. Collectively, Ardisiacrispin B attenuates colitis-associated cancer by rebalancing gut microbiota, suppressing inflammation, and inducing tumor cell apoptosis through inhibition of key oncogenic signaling pathways.

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