Imperatorin exerts anti-colorectal cancer effects by targeting NOX2 to inhibit mast cell degranulation

Colorectal cancer (CRC) is a major global malignancy with a poor prognosis in advanced stages. Aberrant mast cell activation within the tumor microenvironment (TME) drives CRC progression; however, the molecular mechanisms underlying the tumor-promoting role of mast cells in the hypoxic TME remain unclear, and effective therapies targeting these cells are lacking.

To investigate the role of the NADPH oxidase 2 (NOX2)-reactive oxygen species (ROS)-calcium signaling axis in mast cell activation and evaluate the anti-CRC activity of imperatorin (IMP), a natural furanocoumarin.

Human mast cell and CRC cell lines were used to establish hypoxic activation and conditioned medium co-culture systems. Tissue microarrays, single‑cell RNA sequencing (scRNA-seq) datasets and CT26 allograft mouse models were employed, combined with gain/loss-of-function, Western Blot, enzyme-linked immunosorbent assay (ELISA), immunofluorescence and cell functional assays.

NOX2 expression was significantly upregulated in activated mast cells from human CRC tissues. IMP inhibited NOX2, thereby blocking hypoxia-induced oxidative stress and mast cell degranulation. This intervention suppressed the secretion of tumor-promoting mediators and effectively inhibited CRC cell proliferation and invasion. Furthermore, in vivo experiments demonstrated that IMP dose-dependently suppressed CRC allograft growth in murine models without causing overt systemic toxicity.

This study reveals a mechanism by which mast cells promote CRC progression in the hypoxic TME and demonstrates that IMP exerts potent anti-CRC effects by targeting NOX2 to inhibit mast cell activation. These findings identify both a therapeutic target and a promising lead compound for TME-targeted CRC therapy.