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. 2025;28(10):1354-1362.
doi: 10.22038/ijbms.2025.86862.18767.

A20 inhibits doxorubicin-induced macrophage maturation and apoptosis through mTOR signaling in classical Hodgkin lymphoma

Nguyen Xuan Canh  1 , Phan Thi Hoai Trang  2   3 , Pham Thi Huong  4 , Do Thi Trang  4   5 , Pham Viet Nhat  4 , Nguyen Tien Manh  6 , Lê Duy Thành  7 , Nguyen Trung Nam  4 , Nguyen Ba Vuong  2 , Nguyen Thi Xuan  4
Affiliations

A20 inhibits doxorubicin-induced macrophage maturation and apoptosis through mTOR signaling in classical Hodgkin lymphoma

Nguyen Xuan Canh et al. Iran J Basic Med Sci. 2025.

Abstract

Objectives: Classical Hodgkin lymphoma (cHL) is identified by the appearance of Hodgkin and Reed-Sternberg cells. A20 and CYLD are deubiquitinating enzymes involved in negatively regulating NF-κB-mediated immune response. Vincristine (Vinc) and doxorubicin (Dox) are classical antitumor drugs, in which Dox serves a key role in chemotherapy against cHL and Vinc induces disruption of microtubule function that inhibits mitosis of cancer cells. Little is known about the roles of A20/CYLD in regulating macrophage function from cHL patients upon treatment with Vinc or Dox. This study, therefore, asked whether A20/CYLD expression affects function of macrophages in cHL cases.

Materials and methods: Macrophages from cHL patients differentiated from bone marrow cells were exposed to Vinc or Dox. Gene expression levels were determined by real time-qPCR, cell maturation, apoptosis and phagocytosis by flow cytometry, and cytokine release by ELISA.

Results: Dox induced maturation, apoptosis, and phagocytosis of macrophages in cHL cases. Moreover, the percentage of CD68+CD40+, but not CD68+CD86+ cells as well as levels of IL-1β were further enhanced when exposed to A20 siRNA, whereas the absence of CYLD unaltered macrophage function in cHL patients. Importantly, the increased numbers of A20-sensitive CD68+CD40+ and Annexin V-PI+ cells as well as enhanced levels of caspase 3 were abolished in the presence of mTOR inhibitor Everolimus.

Conclusion: The present study indicates that Dox-induced macrophage maturation and apoptosis are dependent on A20 expression through mTOR signaling. Moreover, inhibition of Dox-induced macrophage maturation in the patients with low A20 expression by Everolimus might represent a promising therapy for A20-sensitive cHL cases.

Keywords: A20; Classical hodgkin lymphoma; Everolimus; IL-1β; Macrophages.

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Conflict of interest statement

The authors of this paper declare that they have no financial/commercial conflicts of interests.

Figures

Figure 1
Figure 1
Effects of vincristine and doxorubicin on macrophage maturation and apoptosis in cHL patients
Figure 2
Figure 2
Roles of A20 on doxorubicin-induced macrophage maturation and apoptosis in cHL patients
Figure 3
Figure 3
Effects of mTOR signaling on A20-sensitive doxorubicin-induced macrophage maturation and apoptosis in cHL patients
Figure 4
Figure 4
Effects of vincristine and doxorubicin on macrophage uptake of lymphoma cells from cHL patients
See this image and copyright information in PMC

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