Therapeutic mechanism of Changyong Decoction in suppressing colorectal cancer progression and inducing ferroptosis via the PIEZO1-PI3K/AKT signaling axis

Abstract

Colorectal cancer is a common type of cancer affecting the digestive system. Its development largely results from unbalanced growth and spread of cancerous cells. Changyong Decoction (CYD), a classical traditional Chinese medicine formula, demonstrates therapeutic effects including blood circulation activation, blood stasis elimination, pus elimination, and mass resolution. Nevertheless, its anti-CRC mechanisms remain incompletely elucidated. This study adopted a comprehensive strategy that integrated network pharmacology, UHPLC-MS/MS, molecular docking, and molecular dynamics simulations to systematically predict the active components, targets, and mechanisms of CYD in the treatment of colorectal cancer (CRC). The antitumor efficacy of CYD was further validated through experimental studies. Network pharmacology identified 10 key targets, with KEGG analysis showing significant enrichment of the PI3K/AKT pathway. UHPLC-MS/MS validation confirmed eight primary bioactive compounds. Molecular docking and molecular dynamics simulations confirmed the stable binding between the main bioactive components of CYD and the key target proteins. The anti-colorectal cancer efficacy of CYD was further assessed in vivo using a zebrafish xenograft model. In vitro studies revealed that CYD established a Piezo1-PI3K/AKT regulatory axis that exerts antitumor effects via multiple mechanisms. In this study, we demonstrated that CYD suppressed tumor progression in colorectal cancer cells by inhibiting proliferation and migration, and inducing ferroptosis and apoptosis. These effects were mediated via down-regulation of Piezo1 expression and synergistic inhibition of the PI3K/AKT signaling pathway.