Senolytic Treatment Alleviates Corneal Allograft Rejection Through Upregulation of Angiotensin-Converting Enzyme 2 (ACE2)

  • Invest Ophthalmol Vis Sci. 2025 Feb 3;66(2):15. doi: 10.1167/iovs.66.2.15.
Hao Chi  1  2 ,  Li Ma  1  3 ,  Fanxing Zeng  1  3  4 ,  Xiaolei Wang  1  3 ,  Peng Peng  1  3 ,  Xiaofei Bai  1  3 ,  Ting Zhang  1  3  4 ,  Wenhui Yin  1  3 ,  Yaoyao Yu  1  3  5 ,  Lingling Yang  1  3 ,  Qingjun Zhou  1  3 ,  Chao Wei  1  3  6 ,  Weiyun Shi  1  3  4  7
Affiliations
  • 1. State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, Eye Institute of Shandong First Medical University, Qingdao, China.
  • 2. Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China.
  • 3. School of Ophthalmology, Shandong First Medical University, Jinan, China.
  • 4. Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Eye Institute of Shandong First Medical University, Jinan, China.
  • 5. Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.
  • 6. https://orcid.org/0000-0003-1581-8377.
  • 7. https://orcid.org/0000-0003-4106-373X.
PMID: 39913165 DOI: 10.1167/iovs.66.2.15
Abstract

Purpose: Allograft rejection remains a major cause of failure in high-risk corneal transplants, but the underlying mechanisms are not fully understood. This study aimed to investigate the contribution of transplantation stress-induced cellular senescence to corneal allograft rejection and to elucidate the associated molecular mechanisms.

Methods: Age-matched murine corneal transplantation models were established. Cellular senescence was evaluated using senescence-associated β-galactosidase (SA-β-Gal) staining, western blot, and immunofluorescence staining. The role of cellular senescence in corneal allograft rejection was analyzed using p16 knockout mice and adoptive transfer experiments. Senolytic treatment with ABT-263 was administered intraperitoneally to evaluate its effects on corneal allograft rejection. RNA Sequencing and pharmacological approaches were employed to identify the underlying mechanisms.

Results: Surgical injury induced a senescence-like phenotype in both donor corneas and recipient corneal beds, characterized by an increased accumulation of SA-β-Gal-positive cells in the corneal endothelium and stroma and elevated expression of senescence markers p16 and p21. Using genetic and adoptive transfer models, transplantation stress-induced senescence was shown to exacerbate corneal allograft rejection. Importantly, clearance of senescent cells by ABT-263 significantly suppressed ocular alloresponses and immune rejection. Mechanistically, RNA Sequencing and loss-of-function experiments demonstrated that the anti-rejection effects of senolytic treatment were closely dependent on angiotensin-converting enzyme 2 (ACE2).

Conclusions: These findings highlight transplantation stress-induced senescence as a pivotal pathogenic factor in corneal allograft rejection. Senolytic therapy emerges as a potential novel strategy to mitigate transplant rejection and improve corneal allograft survival.

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