Dual modulation of Wnt and inflammatory pathways by Gingerenone a inhibits colorectal tumorigenesis

Colorectal cancer (CRC) remains a major global health challenge, driven by aberrant activation of the Wnt/β-catenin pathway and persistent inflammatory signaling. Natural bioactive compounds capable of simultaneously targeting these molecular drivers represent an attractive avenue for safer and more effective chemoprevention. This study aimed to evaluate the anti-carcinogenic potential of Gingerenone A (GinA), a diarylheptanoid derived from ginger, by assessing its effects on Wnt/β-catenin signaling, inflammatory mediators, oxidative stress, and apoptosis during colorectal tumorigenesis.

GinA's effects were assessed using HT29 human colorectal adenocarcinoma cells and a 1,2-dimethylhydrazine (DMH)-induced rat model of CRC. In vitro analyses included MTT cytotoxicity, immunofluorescence, and ELISA assays for β-catenin, APC, COX-2, iNOS, and cleaved caspase-3. In vivo, tumor burden, aberrant crypt foci (ACF), histopathology, immunohistochemistry, oxidative stress (ROS), apoptosis (TUNEL), and serum biochemical parameters were evaluated.

GinA treatment significantly reduced HT29 cell viability in a dose- and time-dependent manner, suppressed β-catenin, COX-2, and iNOS expression, enhanced APC expression and caspase-3 expression and activity, and promoted apoptosis. In DMH-treated rats, GinA markedly decreased tumor incidence, ACF number, and dysplasia severity. Molecular and biochemical analyses revealed restoration of APC, downregulation of β-catenin, Wnt5a, COX-2, and iNOS, reduced ROS accumulation, and normalization of hepatic and renal biomarkers.

GinA effectively modulates components of the Wnt/β-catenin pathway and inflammatory signaling, exhibiting antioxidant, anti-inflammatory, and pro-apoptotic properties without systemic toxicity. These results position GinA as a multitarget phytochemical with strong potential for colorectal cancer chemoprevention and adjunctive therapy.