The potential of ruxolitinib as a senomorphic therapy in alleviating neovascular age-related macular degeneration : Ruxolitinib inhibits CNV.
11 affiliations
- 1Department of Ophthalmology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
- 2Key Laboratory of Gastrointestinal Cancer, Fujian Medical University, Ministry of Education, Fuzhou, China.
- 3Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
- 4Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Beijing, 100083, China.
- 5Department of Ophthalmology, Peking University Third Hospital, Beijing, China.
- 6Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan, Shandong, China.
- 7Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
- 8Zhejiang Hailiang Biotechnology Co., Ltd, Hangzhou, Zhejiang, China.
- 9Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Beijing, 100083, China. [email protected].
- 10Department of Ophthalmology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China. [email protected].
- 11Department of Ophthalmology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China. [email protected].
Abstract
Background
Cellular senescence plays a key role in the pathogenesis of neovascular age-related macular degeneration (nAMD). Senomorphic therapy, which targets the senescence-associated secretory phenotype (SASP), holds promise for treating age-related diseases; however, effective senomorphic treatments for nAMD remain lacking.Methods
We screened a panel of senomorphic agents in bleomycin- and ionizing radiation (IR)-induced senescent ARPE-19 cells to identify a lead compound for nAMD. Bulk and single-cell RNA sequencing data were analyzed to explore JAK-STAT signaling activation. Ruxolitinib and siRNA were used to validate the role of the JAK1/2-STAT3 pathway in senescent retinal pigment epithelium (RPE). A laser-induced choroidal neovascularization (CNV) model was established in Brown-Norway rats for in vivo studies.Results
Ruxolitinib, a JAK1/2 inhibitor, most effectively suppressed SASP factors and complement C3 expression while restoring pigment epithelium-derived factor (PEDF) levels in senescent ARPE-19 cells. Knockdown of JAK1 or JAK2 significantly reversed the expression of vascular endothelial growth factor (VEGF), C3, and PEDF. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) revealed activation of the JAK-STAT pathway in nAMD patient samples, CNV models, and senescent RPE cells, which was corroborated in the CNV rat model. Inhibition of JAK1/2-STAT3 with ruxolitinib markedly reduced vascular leakage and CNV area, and accelerated recovery of retinal function. The combination of ruxolitinib with anti-VEGF therapy presented a better effect on inhibiting CNV area. Furthermore, intravitreal injection of ruxolitinib showed no significant structural or functional toxicity in normal rat retinas over one month.Conclusions
Our study identifies the JAK1/2-STAT3 pathway as a key regulator of the SASP in senescent RPE and confirms its activation in nAMD and experimental CNV. Pharmacologic inhibition of this pathway with ruxolitinib effectively attenuates CNV progression with a favorable short-term safety profile, supporting its potential as a senomorphic therapy for nAMD.
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BibTeX
@article{wang2026potential,
title = {{The potential of ruxolitinib as a senomorphic therapy in alleviating neovascular age-related macular degeneration : Ruxolitinib inhibits CNV.}},
author = {Yinhao Wang and Zhihua Huang and Yulin Tseng and Huiling Ma and Kuangqi Chen and Xinlei Pan and Hui Ye and Tiantian Cheng and Jiayun Ge and Jingcheng Deng and Xinglin Wang and Jianhua Xia and Jianqin Shen and Chixin Du and Wei Lei and Zebin Mao and Hongguang Cui and Yan Sheng},
journal = {Journal of translational medicine},
year = {2026},
month = jul,
doi = {10.1186/s12967-026-08705-x},
url = {https://europepmc.org/article/MED/42928338},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - The potential of ruxolitinib as a senomorphic therapy in alleviating neovascular age-related macular degeneration : Ruxolitinib inhibits CNV.
AU - Yinhao Wang
AU - Zhihua Huang
AU - Yulin Tseng
AU - Huiling Ma
AU - Kuangqi Chen
AU - Xinlei Pan
AU - Hui Ye
AU - Tiantian Cheng
AU - Jiayun Ge
AU - Jingcheng Deng
AU - Xinglin Wang
AU - Jianhua Xia
AU - Jianqin Shen
AU - Chixin Du
AU - Wei Lei
AU - Zebin Mao
AU - Hongguang Cui
AU - Yan Sheng
PY - 2026
DA - 2026/07/01
JO - Journal of translational medicine
DO - 10.1186/s12967-026-08705-x
UR - https://europepmc.org/article/MED/42928338
AB - Background Cellular senescence plays a key role in the pathogenesis of neovascular age-related macular degeneration (nAMD). Senomorphic therapy, which targets the senescence-associated secretory phenotype (SASP), holds promise for treating age-related diseases; however, effective senomorphic treatments for nAMD remain lacking.Methods We screened a panel of senomorphic agents in bleomycin- and ionizing radiation (IR)-induced senescent ARPE-19 cells to identify a lead compound for nAMD. Bulk and single-cell RNA sequencing data were analyzed to explore JAK-STAT signaling activation. Ruxolitinib and siRNA were used to validate the role of the JAK1/2-STAT3 pathway in senescent retinal pigment epithelium (RPE). A laser-induced choroidal neovascularization (CNV) model was established in Brown-Norway rats for in vivo studies.Results Ruxolitinib, a JAK1/2 inhibitor, most effectively suppressed SASP factors and complement C3 expression while restoring pigment epithelium-derived factor (PEDF) levels in senescent ARPE-19 cells. Knockdown of JAK1 or JAK2 significantly reversed the expression of vascular endothelial growth factor (VEGF), C3, and PEDF. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) revealed activation of the JAK-STAT pathway in nAMD patient samples, CNV models, and senescent RPE cells, which was corroborated in the CNV rat model. Inhibition of JAK1/2-STAT3 with ruxolitinib markedly reduced vascular leakage and CNV area, and accelerated recovery of retinal function. The combination of ruxolitinib with anti-VEGF therapy presented a better effect on inhibiting CNV area. Furthermore, intravitreal injection of ruxolitinib showed no significant structural or functional toxicity in normal rat retinas over one month.Conclusions Our study identifies the JAK1/2-STAT3 pathway as a key regulator of the SASP in senescent RPE and confirms its activation in nAMD and experimental CNV. Pharmacologic inhibition of this pathway with ruxolitinib effectively attenuates CNV progression with a favorable short-term safety profile, supporting its potential as a senomorphic therapy for nAMD.
SN - 1479-5876
ER -