2. Academic Validation
  3. Indole-3-carbinol inhibits PD-L1-mediated immune evasion in hepatocellular carcinoma via suppressing NF-κB p105 Ubiquitination

Indole-3-carbinol inhibits PD-L1-mediated immune evasion in hepatocellular carcinoma via suppressing NF-κB p105 Ubiquitination

  • Phytomedicine. 2025 Jun:141:156692. doi: 10.1016/j.phymed.2025.156692.
Yongkang Wu 1,  Qing Tao 1,  Jing Xie 1,  Xiao Liu 1,  Yuanzhi Zhou 1,  Chengyan Wei 1,  Chunwei Zhang 1,  Jingjing Wang 1,  Yong Jin 2
Affiliations

Affiliations

  • 1 Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, 230032, Hefei, PR China; Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of National Education, Anhui Medical University, 230032, Hefei, PR China.
  • 2 Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, 230032, Hefei, PR China; Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of National Education, Anhui Medical University, 230032, Hefei, PR China. Electronic address: jinyong@ahmu.edu.cn.
PMID: 40215823 DOI: 10.1016/j.phymed.2025.156692
Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and immunotherapy has demonstrated significant therapeutic benefit in HCC. Indole-3-carbinol (I3C), a naturally occurring ingredient of Cruciferous vegetables, significantly inhibits the growth of a wide range of tumors. However, its mechanism of action has not been fully elucidated.

Purpose: This study aims to verify and explore the immunomodulatory effect of I3C in HCC models, and to investigate the specific role and mechanism by which I3C affects PD-L1 expression through the ubiquitination of NF-κB p105.

Methods: In vitro, I3C was treated with HepG2 cells and relevant indicators were analyzed. In vivo, the mouse HCC model was established and the effect of I3C on tumors and immune function was evaluated. Subsequently, the downstream target of I3C was found through target prediction, molecular docking, and molecular dynamics simulation. Finally, combined therapy was used to further investigate the effect of I3C on mouse HCC tumors.

Results: We observed that I3C resulted in decreased programmed cell death ligand 1 (PD-L1) expression in HepG2 cells and increased CD8 T cell infiltration in tissues. Subsequently, target prediction and molecular docking demonstrated that I3C was able to efficiently bind to NF-κB p105. In addition, overexpression of NF-κB p105 upregulated PD-L1 expression and almost completely eliminated the inhibitory effect of I3C. Notably, the combination of I3C and PD-L1 monoclonal antibodies showed synergistic anti-tumor effects in the mouse HCC model.

Conclusion: This study demonstrated that I3C inhibits PD-L1-mediated immune evasion in HCC via suppressing NF-κB p105 ubiquitination. The role of I3C in tumors deserves further investigation and provides the foundation for the future development of novel immunotherapeutic drugs.

Keywords

Hepatocellular carcinoma; Immune checkpoint; Immune evasion; Indole-3-carbinol; Nf-κb p105; Pd-l1.

Figures
Products