Published online Nov 15, 2026. doi: 10.4251/wjgo.121010
Revised: June 19, 2026
Accepted: August 14, 2026
Published online: November 15, 2026
Processing time: 185 Days and 10.2 Hours
Chronic constipation-associated inflammation is a global public health threat as end-stage colorectal malignancy continues to rise worldwide. Aberrant innate immune signaling, especially via NOD-like receptor protein 3 (NLRP3) inflammasome–caspase-1-interleukin-1 beta (IL-1β) cascade, has emerged as a molecular driver of chronic colonic epithelial inflammation in response to prolonged ex
To investigate whether ASP inhibits the NLRP3/caspase-1/IL-1β inflammasome signaling pathway to attenuate deoxycholic acid (DCA)-induced chronic colonic epithelial inflammation and early neoplastic transformation, thereby establishing a mechanistic basis for ASP as a chemopreventive candidate against constipation-associated colorectal cancer.
NCM460 cells – a well-characterized normal human colon mucosal epithelial cell line, were exposed separately to vehicle control, or used as osmotic control and treated with vehicle plus equimolar sodium chloride, or 200 μM DCA and co-treated with ASP at 2 increasing concentrations (ASP-L and ASP-H). Nigericin, a classical NLRP3 activator that was used to reinvite inflammasome activity, and a series of selective pharmacological probes – the NLRP3-specific inhibitors MCC950 and cycplase 09, the potassium ionophore nigericin as well as the caspase-1 selective inhibitor VX-765 – were utilized for mechanistic dissection. Immunofluorescence was used to determine the localization and abundance of NLRP3, ASC, and cleaved caspase-1. Reverse-transcription PCR and ELISA were used to measure messenger RNA and secreted protein levels of IL-1β, IL-18, tumor necrosis factor-alpha, IL-6, COX-2 and matrix metalloproteinase-9. Markers of epithelial-mesenchymal transition and cellular proliferation were further examined to determine early neoplastic transformation.
DCA challenge remarkably induced the expression of NLRP3, ASC and cleaved caspase-1 as well as all six downstream inflammatory mediators at both transcript and protein levels in NCM460 cells, along with up-regulating epithelial-mesenchymal transition marker genes and promoting cell proliferation. The changes to these parameters were dose-dependently reversed by ASP; in the case of the third exposure (higher concentration), all parameters were close to baseline levels. The activation of caspase-1 and IL-1beta by Nigericin was restored in the presence of ASP, but co-treating with either MCC950 or VX-765 completely inhibited this rebound proven that NLRP3/caspase-1 pathwayspecifiselectivity. Cycplase 09 and VX-765 significantly suppressed all six inflammatory mediators in ASP + nigericin cultures, as confirmed by reverse-transcription PCR and ELISA analyses.
ASP inhibits the NLRP3/caspase-1/IL-1β pathway and protects DCA-induced inflammatory injury of colonic epithelial cells and early neoplastic transformation in vitro. These mechanistic insights warrant additional preclinical and clinical testing of ASP as a chemopreventive agents for constipation-related colorectal cancer risk.
Core Tip: Chronic constipation has lately been considered a possible risk factor for colorectal cancer due to prolonged colonic transit time and retention of secondary bile acids, e. g., deoxycholic acid, which can lead to persistent epithelial inflammation. Here, we present that a bioactive component of the traditional Chinese medicine Yang-Gui [Angelica sinensis polysaccharide (ASP)] can effectively suppress deoxycholic acid-induced inflammatory processes in human colonic epithelial cells. Mechanistically, ASP is able to inhibit activation of the NOD-like receptor protein 3 inflammasome and its downstream cascades caspase-1/interleukin-1β signaling pathway, thereby reducing the production of several pro-inflammatory mediators in early colorectal carcinogenesis. Our findings give mechanistic support for ASP as a potential natural candidate for preventing inflammation-driven colonic carcinogenesis under chronic constipated condition.