Hua-Zhuo-Jie-Du formula alleviates colitis-associated colorectal cancer via regulating phosphatidylinositol 3-kinase/protein kinase B signaling pathway

BACKGROUND Colitis-associated colorectal cancer (CAC) is a common type of malignant tumor that occurs in the digestive tract and poses a significant threat to human health. The traditional Chinese medicine preparation Hua-Zhuo-Jie-Du formula (HZJDF) has shown clinical efficacy in preventing CAC; however, the potential therapeutic mechanisms of this formula for treating CAC remain under explored. AIM To investigate the therapeutic efficacy and mechanism of HZJDF against CAC through applying an integrated research approach. METHODS We first established a CAC mouse model using the azoxymethane/dextran sulfate sodium induction method and then assessed the therapeutic effects of various doses of HZJDF on the CAC mice. Subsequently, we utilized a combination of network pharmacology and transcriptomics analyses to help predict the potential mechanisms by which HZJDF acts against CAC. Finally, we sought to validate these prediction findings through animal and cell experiments. RESULTS HZJDF significantly mitigated weight reduction and colon length shortening in a dose-dependent manner, enhanced the mice survival rates, lowered the disease activity index scores, diminished the tumor incidence and burden, and improved the pathological condition of the colon tissues in the CAC mice. The findings from the network pharmacology and transcriptomics analyses suggested that the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway might be the potential mechanism through which HZJDF exerts its protective effects against CAC. In vivo studies showed that HZJDF diminished the quantity of Ki67-positive cells within the colon tissues of the CAC mice and lowered the levels of phosphorylated PI3K and AKT proteins. Meanwhile, in vitro studies indicated that serum containing HZJDF decreased the viability, proliferation, and migration of HT-29 and HCT116 cells in a dose-dependent manner, while also lowering the expression of key proteins linked to the PI3K/AKT signaling pathway. CONCLUSION HZJDF effectively alleviated CAC tumorigenesis by suppressing the PI3K/AKT signaling pathway, providing reliable evidence to support the appropriate utilization of HZJDF in CAC treatment.