Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Imperatorin exerts anti-colorectal cancer effects by targeting NOX2 to inhibit mast cell degranulation.
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Shi Xianpeng, Zhang Peng, Cui Xia, Hou Yajing, Zhang Dan, Zhao Ying, Cao Lu, Yong Suyun, Zhou Nan, Wang Jianhua
Аннотация
BACKGROUND: 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.