Integrated Multi-Omics Elucidates the Therapeutic Potential and Mechanisms of Andrographolide in Colorectal Cancer

Abstract

Colorectal cancer (CRC) remains a major clinical challenge owing to its high mortality and limited therapeutic options, highlighting the urgent need for novel anticancer agents. Andrographolide (AGL), the principal bioactive compound isolated from the medicinal herb Andrographis paniculata, has demonstrated promising anticancer activity across multiple malignancies; however, its effects on CRC and the underlying molecular mechanisms remain poorly elucidated. Here, we systematically evaluated the anti-CRC potential of AGL using both in vitro and in vivo models. AGL significantly inhibited the proliferation of HT-29 and HCT-116 CRC cell lines in a dose- and time-dependent manner, induced G1-phase cell cycle arrest, suppressed cell migration, and promoted apoptosis and necrosis as determined by CCK-8 assays, flow cytometry, wound-healing assays, and YO-PRO-1/propidium iodide dual staining. Integrated transcriptomic and proteomic analyses of AGL-treated HT-29 cells revealed extensive gene and protein alterations enriched in pathways governing cell cycle control, apoptosis, and cancer-related signaling, and Western blotting confirmed the upregulation of pro-apoptotic proteins and downregulation of anti-apoptotic proteins. Importantly, AGL also significantly suppressed tumor growth in an HT-29 subcutaneous xenograft mouse model. Collectively, these findings demonstrate that AGL exerts potent anti-CRC activity primarily through the induction of G1-phase arrest and apoptosis, supporting its potential as a promising natural lead compound for the development of novel CRC therapeutics.