1. Academic Validation
  2. Cucurbitacin B suppresses malignant progression of oral leukoplakia via ferroptosis-induced macrophage polarization

Cucurbitacin B suppresses malignant progression of oral leukoplakia via ferroptosis-induced macrophage polarization

  • Int Immunopharmacol. 2025 Sep 13:165:115485. doi: 10.1016/j.intimp.2025.115485.
Chen Cheng 1 Jiawei Chai 1 Heng Zhang 1 Yajun Wang 1 Lin Zhang 1 Mengyuan Yang 1 Xin Chen 1 Qi Jiang 1 Hui Ren 1 YaHsin Cheng 2 Fang Zhang 3
Affiliations

Affiliations

  • 1 Shanxi Medical University School and Hospital of Stomatology, Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, No.63 Xinjian South Road, Yingze District, Taiyuan, Shanxi 030001, China.
  • 2 Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan.
  • 3 Shanxi Medical University School and Hospital of Stomatology, Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, No.63 Xinjian South Road, Yingze District, Taiyuan, Shanxi 030001, China. Electronic address: zhangfangdoctor@sxmu.edu.cn.
Abstract

M2 macrophage, which can promote oral leukoplakia (OLK) development and progression, is considered a new potential target for the treatment and prevention of OLK malignant progression. Cucurbitacin B (CuB), a tetracyclic triterpenoid compound widely found in cucurbit Plants, has shown promising immunomodulatory and anti-proliferative efficacy in previous studies. However, whether CuB can inhibit OLK malignant progression by modulating M2 macrophage polarization remains unclear. This study aims to investigate the role of CuB in regulating M2 macrophage polarization in inhibiting the malignant progression of OLK and further explore its potential mechanism of action. In vivo experiments showed that CuB significantly inhibited 4NQO-induced malignant progression of OLK to oral squamous cell carcinoma (OSCC) in C57BL/6 mice. In mice OLK tissues, CuB decreased the number of M2 macrophages but increased the number of M1 macrophages. Bioinformatics and in vitro experiments showed that CuB appears to activate Ferroptosis in M2 macrophages by promoting Fe2+ accumulation, down-regulating GPX4 and SLC7A11, and up-regulating COX-2 expression. The resulting Ferroptosis products, including MDA, ROS, and LPO, may contribute to the remodeling of M2 macrophages into an M1 phenotype. Furthermore, in vitro indirect co-culture experiments indicate that CuB-activated Ferroptosis in M2 macrophages significantly inhibited the proliferation of dysplastic oral keratinocyte (DOK) cells. In conclusion, CuB can inhibit the malignant progression of OLK, and ferroptosis-induced macrophage polarization may play a key role in this process. This study provides new insights into the application of CuB in the immunotherapy of OLK.

Keywords

Cucurbitacin B; Ferroptosis; Immunotherapy; M2 macrophage; Macrophage polarization; Oral leukoplakia.

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