Verbascoside inhibits ovarian cancer proliferation via IRAK4-CXCL5 axis-mediated suppression of neutrophil infiltration and neutrophil extracellular trap formation.

Authors

Yu Ren, Tianyi Yu, Zhijie Wang, Yuzhen Ma, Jinying He

Published in

Cancer letters. Pages 218901. Oct 16, 2026. Epub Oct 16, 2026.

Abstract

The specific mechanisms of Verbascoside (VB) in ovarian cancer (OC) remain insufficient. This study aimed to explore the anti-tumor mechanisms of VB in OC, focusing on its ability to modulate the immunosuppressive tumor microenvironment (TME), particularly through targeting neutrophil infiltration and neutrophil extracellular traps (NETs). The anti-tumor and anti-NETosis efficacy of VB was evaluated in vivo using subcutaneous, orthotopic, and pulmonary metastasis mouse models of OC. Microproteomics and bioinformatics analysis identified the direct molecular target of VB and the key neutrophil chemoattractant. The underlying mechanisms were validated in vitro and in vivo (using SKOV3, ID8, and neutrophils), alongside loss-of-function approaches. The combination of VB with anti-PD-1 immunotherapy was also assessed. VB inhibited OC proliferation/metastasis, promoted anti-tumor immunity, and suppressed neutrophil infiltration and NETosis. Neutrophil depletion attenuated VB's anti-metastatic effect. Microproteomics and bioinformatics screening identified IRAK4 as a direct molecular target of VB and CXCL5 as a key neutrophil chemoattractant. SPR confirmed the direct binding between VB and IRAK4, and molecular docking revealed specific hydrogen bond interactions. Mechanistically, VB treatment or IRAK4 knockdown suppressed CXCL5 expression, and consequently reduced neutrophil infiltration and NETosis. Consistently, CXCL5 overexpression abrogated the inhibitory effects of VB on neutrophil NETosis and recruitment. Furthermore, VB synergized with anti-PD-1 therapy, thereby achieving superior tumor growth inhibition, reduced Ki67 expression, and enhanced CD8⁺ T cell infiltration. In conclusion, VB exerts potent anti-tumor effects in OC by targeting the IRAK4/CXCL5 axis, thereby inhibiting neutrophil infiltration and NETosis, reshaping the immunosuppressive TME, and restoring anti-tumor immunity.

PMID:
42887866
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.

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