2. Academic Validation
  3. Hypericin impedes M2 macrophage polarization and protects against Hepatocellular carcinoma

Hypericin impedes M2 macrophage polarization and protects against Hepatocellular carcinoma

  • Mol Immunol. 2025 May:181:160-168. doi: 10.1016/j.molimm.2025.03.012.
Xinru Wen 1,  Xianling Wang 2,  Qing Yao 1,  Simin Chen 2,  Chengwei Li 2,  Congyang Zheng 2,  Ang Huang 3,  Xiaoyan Zhan 4,  Zhaofang Bai 5,  Xiaohe Xiao 6
Affiliations

Affiliations

  • 1 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China.
  • 2 Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China.
  • 3 Department of Gastroenterology and Hepatology, the First Medical Center of PLA General Hospital, China.
  • 4 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China; National Key Laboratory of Kidney Diseases, Beijing 100005, China. Electronic address: xyzhan123@163.com.
  • 5 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China; National Key Laboratory of Kidney Diseases, Beijing 100005, China. Electronic address: baizf2008@hotmail.com.
  • 6 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China; National Key Laboratory of Kidney Diseases, Beijing 100005, China. Electronic address: pharmacy_302@126.com.
PMID: 40153953 DOI: 10.1016/j.molimm.2025.03.012
Abstract

Background: There has been increasing evidence that M2 polarization, which is essential for tumor growth, is present in most tumor-associated macrophages. Hypericin is the major component of the Traditional Chinese Medicine Hypericum perforatum. Hypericin exhibits antitumor activities, but its regulation on M2 macrophage polarization and the protective against Hepatocellular carcinoma (HCC) remains unknown.

Methods: IL-4 was used to induce bone marrow-derived macrophages (BMDMs) to differentiate into M2 macrophages, the effect of hypericin on M2 polarization of BMDMs was investigated, mRNA level of M2-related genes was determined using RT-qPCR and flow cytometry. Furthermore, the effect of culture medium of M2 macrophage (M2-CM) pretreated with hypericin or not on the proliferation, migration, and invasion of Hepa1-6 cells was studied. To investigate the mechanism, the PI3K/Akt signaling pathway, which is critical in macrophage polarization was tested. A mouse model of HCC was established by subcutaneous implantation of H22 cells, the impact of Hyp on tumor growth and M2 macrophage polarization in tumor tissues was identified.

Results: In the present study, we found that Hyp significantly inhibited M2 polarization of macrophages, as indicated by decreased expression of CD206 and M2-related markers, moreover, Hyp suppressed the M2-CM-induced proliferation, invasion and migration of Hepa1-6 cells. Hyp manifested an inhibitory effect on the PI3K/Akt signaling pathway during the differentiation of M2 macrophages. In vivo experiments showed that Hyp greatly suppressed tumor growth and reduced M2 macrophage polarization in tumor tissues.

Conclusion: Hyp impedes the growth, proliferation, invasion and migration of HCC by inhibiting M2 macrophages polarization via the PI3K/Akt signaling pathway, our data demonstrate that hypericin may be a promising candidate for HCC treatment.

Keywords

Hepatocellular carcinoma; Hypericin; M2 macrophage polarization; PI3K/AKT signaling pathway.

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