Abstract
This study elucidated the mechanistic role of the Suppressor of Cytokine Signaling 5 (SOCS5) in diabetic retinopathy (DR), focusing on DNA damage and cellular senescence pathways. Utilizing both in vitro (high glucose (HG)-induced human retinal microvascular endothelial cells (HRMECs)) and in vivo (streptozotocin-induced DR mouse models) approaches, we demonstrated that SOCS5 was significantly upregulated in DR. SOCS5 knockdown mitigated retinal tissue damage, vascular leakage, and apoptosis in DR mice while reducing DNA damage and cellular senescence in HG-stimulated HRMECs. Mechanistically, SOCS5 promoted DR progression by regulating the expression of Cyclin-Dependent Kinase Inhibitor 1 A (CDKN1A), a key mediator of cell cycle arrest and senescence. Furthermore, we identified POU Class 2 Homeobox 1 (POU2F1) as an upstream transcriptional activator of SOCS5, forming a novel POU2F1-SOCS5-CDKN1A axis that drove DR pathogenesis. Inhibition of POU2F1 and SOCS5 ameliorated DR-related pathology in mice, suggesting a novel therapeutic strategy. These findings reveal a previously unrecognized signaling pathway in DR and highlight SOCS5 as a promising target for intervention.
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Funding
This work was supported by Yunnan Fundamental Research Projects (grant NO. 202301AT070092), Priority Union Foundation of Yunnan Provincial Science and Technology Department and Kunming Medical University (grant NO. 202201AY070001-077), Yunnan Provincial Youth Talent Research (grant NO. RLQB20220002), 535 Talent Project of First Affiliated Hospital of Kunming Medical University (grant NO. 2023535D19) the First-Class Discipline Team of Kunming Medical University (grant NO. 2024XKTDTS01) and Key Clinical Specialty of Ophthalmology in Yunnan Province (grant NO. 300070).
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Di Yang: Conceptualization, Methodology, Writing—review and editing. Siduo Lu: Data curation, Formal analysis, Writing—original draft. Hongmei Liu: Investigation, Formal analysis. You Zhou: Investigation, Data curation. Hua Zhong: Conceptualization, Methodology, Writing - review & editing.
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Yang, D., Lu, S., Liu, H. et al. Mechanistic insights into SOCS5-related DNA damage and cellular senescence in diabetic retinopathy. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03011-3
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DOI: https://doi.org/10.1038/s41420-026-03011-3
