Natural killer cell-derived granzyme B as a therapeutic target for alleviating graft injury during liver transplantation

  • Acta Pharm Sin B. 2025 Oct;15(10):5277-5293. doi: 10.1016/j.apsb.2025.07.042.
Kai Wang  1 ,  Zhoucheng Wang  2 ,  Xin Shao  3  4 ,  Lijun Meng  5 ,  Chuanjun Liu  6 ,  Nasha Qiu  5  7 ,  Wenwen Ge  2 ,  Yutong Chen  7 ,  Xiao Tang  2 ,  Xiaodong Wang  7 ,  Zhengxing Lian  5 ,  Ruhong Zhou  8  9 ,  Shusen Zheng  10  11 ,  Xiaohui Fan  3  4 ,  Xiao Xu  1  11
Affiliations
  • 1. General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310024, China.
  • 2. Department of Surgery, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 3. Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 4. National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314103, China.
  • 5. Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China.
  • 6. College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 7. The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China.
  • 8. Institute of Quantitative Biology, Shanghai Institute for Advanced Study, College of Life Sciences, Zhejiang University, Hangzhou 310027, China.
  • 9. Department of Chemistry, Columbia University, New York, NY 10027, USA.
  • 10. Shulan Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310015, China.
  • 11. NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China.
PMID: 41132839 DOI: 10.1016/j.apsb.2025.07.042
Abstract

Liver transplantation (LT) has become a standard treatment for end-stage liver diseases, and graft injury is intricately associated with poor prognosis. Granzyme B (GZMB) plays a vital role in natural killer (NK) Cell Biology, but whether NK-derived GZMB affects graft injury remains elusive. Through the analysis of single-cell RNA-sequencing data obtained from human LT grafts and the isolation of lymphocytes from mouse livers following ischemia-reperfusion injury (IRI), we demonstrated that 2NK cells with high expression of GZMB are enriched in patients and mice. Both systemically and liver-targeted depletion of NK cells led to a notable reduction in GZMB+ cell infiltration, subsequently resulting in diminished graft injury. Notably, the reconstitution of Il2rg -/- Rag2 -/- mice with purified Gzmb-KO NK cells demonstrated superior outcomes compared to those with wild-type NK cells. Crucially, global knockout of GZMB and pharmacological inhibition exhibited remarkable improvements in liver function in both mouse IRI and rat LT models. Moreover, a phosphorylated derivative of FDA-approved vidarabine was identified as an effective inhibitor of mouse GZMB activity by molecular dynamics, which could provide a potential avenue for therapeutic intervention. Therefore, targeting NK cell-derived GZMB during the LT process suggests potential therapeutic strategies to improve post-transplant outcomes.

Keywords
Adoptive immunotherapy; Granzyme B; Hepatic ischemia-reperfusion injury; Liver transplantation; Molecular dynamics; Nanomedicine; Natural killer cells; Translational medicine.
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