2. Academic Validation
  3. Pomalidomide promotes macrophage control of Mycobacterium tuberculosis via enhancing HDAC6-mediated autophagy

Pomalidomide promotes macrophage control of Mycobacterium tuberculosis via enhancing HDAC6-mediated autophagy

  • Int Immunopharmacol. 2025 Jun 17:158:114831. doi: 10.1016/j.intimp.2025.114831.
Fuzhen Zhang 1,  Yu Dong 2,  Zeliang Yang 2,  Can Guo 3,  Xuxia Zhang 2,  Yuanyuan Shang 2,  Liang Li 1,  Mengqiu Gao 4,  Yu Pang 5
Affiliations

Affiliations

  • 1 Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, PR China; Department of Epidemiology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, PR China.
  • 2 Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, PR China.
  • 3 Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, PR China; The Two Department of Tuberculosis, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China.
  • 4 Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, PR China. Electronic address: gaomqwdm@aliyun.com.
  • 5 Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, 101149, PR China. Electronic address: pangyupound@163.com.
PMID: 40373598 DOI: 10.1016/j.intimp.2025.114831
Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a critical global health challenge. The development of new anti-tuberculosis drugs that can target the host immune system to clear intracellular Mtb is essential for TB control. Individuals known as resisters exhibit natural resistance to TB Infection, offering a valuable model for exploring novel therapeutic targets. Our previous research has identified Histone Deacetylase 6 (HDAC6) as a key mediator of the innate immune responses in resisters against Mtb Infection. In this study, we demonstrated that pomalidomide, an immunomodulatory drug, enhanced HDAC6 expression under Mtb Infection and promoted Autophagy and acidification of Mtb-containing phagosomes, thus reducing Mtb survival within macrophages. Importantly, pomalidomide enhanced Autophagy in a manner dependent on HDAC6. Additionally, pomalidomide inhibited the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and blocked the degradation of the key NF-κB pathway protein IκBα. In Mtb-infected mouse models, we observed that pomalidomide increased HDAC6 levels and autophagy-related gene expression in the lung of mice, reducing Bacterial loads in the lung and spleen and alleviating inflammatory responses. In conclusion, our findings suggest that pomalidomide resists intracellular Mtb Infection through HDAC6-mediated Autophagy pathway, positioning it as a promising candidate for TB immunotherapy.

Keywords

Autophagy; Histone deacetylase 6; Immunotherapy; Mycobacterium tuberculosis; Pomalidomide; Tuberculosis.

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