Naringenin suppresses colorectal Cancer progression by targeting the Gankyrin/PI3K /AKT/GSK-3β/β-catenin signaling Axis.

Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies worldwide. Natural products derived from Traditional Chinese Medicine (TCM), offer promising therapeutic potential due to their multitarget effects and low toxicity. Naringenin (NAR), a major flavonoid found in citrus peel (chenpi), has shown anticancer activity in several tumor types; however, its mechanism in CRC remains incompletely understood. We combined network pharmacology, molecular docking, and experimental validation to explore the anti-CRC mechanisms of NAR. Bioinformatics databases were used to identify overlapping targets between NAR and CRC. Enrichment analyses and protein-protein interaction (PPI) networks were performed. The interaction between NAR and core targets was confirmed via molecular docking. In vitro assays (CCK-8, colony formation, flow cytometry, Transwell) and Western blotting were used to assess the functional and molecular effects of NAR and Gankyrin modulation. In vivo efficacy and toxicity were evaluated using a CRC xenograft model in nude mice. Network pharmacology identified AKT1 as a hub target, and pathway enrichment highlighted PI3K-AKT signalling. Naringenin (NAR) dose-dependently suppressed colorectal cancer (CRC) cell proliferation, migration and invasion, while promoting apoptosis. In vivo, NAR significantly inhibited tumour growth without overt systemic toxicity. Mechanistically, NAR attenuated the Gankyrin-PI3K-AKT-GSK-3β-β-catenin axis. In gain-of-function rescue experiments, Gankyrin overexpression partially blunted the anti-proliferative and anti-invasive effects of NAR, supporting a Gankyrin-dependent component of NAR activity. This study reveals that NAR exerts anti-CRC effects by targeting the Gankyrin/ PI3K/AKT/GSK-3β/β-catenin pathway, supporting its potential as a safe and effective therapeutic agent in CRC treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10616-026-00948-2.