Zahi Hussain

Background: Diabetic retinopathy (DR) and ischemic retinopathy are among the most common causes of irreversible vision loss worldwide. Current standard-of-care treatments, including anti-VEGF therapy and surgical intervention, target late-stage disease manifestations and fail to address the neuroinflammatory and neurodegenerative processes that begin much earlier in disease progression.^1,5 Necroptosis — a regulated, pro-inflammatory form of programmed cell death mediated by receptor-interacting protein kinases 1 and 3 (RIP1/RIP3) and mixed lineage kinase domain-like protein (MLKL) — has emerged as a critical but underexplored mechanism in retinal disease.^1-3 Microglia, the resident immune cells of the retina, appear to be the primary cell type undergoing this process in response to hyperglycemia and hypoxia, releasing pro-inflammatory cytokines and angiogenic factors that worsen tissue injury.^1,2 Understanding the role of microglial necroptosis in driving retinal inflammation and neurodegeneration may identify new therapeutic targets for earlier and more effective intervention in diabetic eye disease.

Objective: This literature review investigates whether RIP3-mediated microglial necroptosis is a central driver of neuroinflammation, pathological angiogenesis, and retinal ganglion cell (RGC) degeneration across diabetic and ischemic retinopathy, and it evaluates the translational relevance of these findings to human disease.

Search Methods: A literature search was conducted using PubMed with search terms including “necroptosis,” “diabetic retinopathy,” “RIP3,” “MLKL,” “microglia,” “retinal neurodegeneration,” and “ischemic retinopathy.” Five primary studies published between 2018 and 2026 were selected, encompassing murine STZ-induced diabetic models, oxygen-induced retinopathy models, retinal ischemia/reperfusion models, glutamate excitotoxicity glaucoma models, and a clinical observational study measuring cytokine and VEGF levels in human DR patients.^1-5

Results: RIP3-mediated necroptosis was consistently activated in retinal microglia across multiple disease models. In early DR, hyperglycemia triggered RIP1/RIP3/MLKL-dependent microglial death and release of pro-inflammatory cytokines including TNF-α, IL-1β, and MCP-1; pharmacological RIP3 inhibition with GSK-872 reduced neuroinflammation and preserved visual function.¹ Single-cell RNA sequencing identified a distinct necroptotic microglial subpopulation in ischemic retinas that released FGF2, driving pathological angiogenesis through a mechanism independent of VEGF.² Combined necroptosis and VEGF blockade produced greater antiangiogenic effects than either treatment alone.² In a retinal ischemia/reperfusion model, the selective RIPK3 inhibitor GSK840 reduced necroptotic RGC death and preserved both retinal structure and electroretinographic function.³ In a glutamate excitotoxicity glaucoma model, necroptosis inhibition additionally suppressed NLRP3 inflammasome activation, revealing a secondary mechanism by which the RIP1/RIP3/MLKL pathway amplifies retinal neuroinflammation.⁴ Clinical data from DR patients confirmed significantly elevated levels of IL-1β, TNF-α, and VEGF in both the aqueous humor and serum, directly mirroring the cytokine profiles observed in animal models.⁵

Conclusion: RIP3-mediated necroptosis in retinal microglia and RGCs represents a mechanistically coherent and therapeutically actionable pathway in DR and related ischemic retinal diseases.^1-4 RIP3 inhibitors consistently reduce neuroinflammation, neurodegeneration, and pathological angiogenesis across multiple experimental models, and human cytokine data support the clinical relevance of these findings.⁵ Future research should evaluate the safety and dosing of intravitreal RIP3 inhibitors in humans and determine whether combining necroptosis blockade with anti-VEGF therapy provides meaningful clinical benefit beyond current standards of care.^2,5-8

Works Cited:

1. Huang Z, Liang J, Chen S, et al. RIP3-mediated microglial necroptosis promotes neuroinflammation and neurodegeneration in the early stages of diabetic retinopathy. Cell Death Dis. 2023;14(3):227. Published 2023 Mar 29. doi:10.1038/s41419-023-05660-z
2. He C, Liu Y, Huang Z, et al. A specific RIP3+ subpopulation of microglia promotes retinopathy through a hypoxia-triggered necroptotic mechanism. Proc Natl Acad Sci U S A. 2021;118(11):e2023290118. doi:10.1073/pnas.2023290118
3. Feng Y, Hu C, Cui K, et al. GSK840 Alleviates Retinal Neuronal Injury by Inhibiting RIPK3/MLKL-Mediated RGC Necroptosis After Ischemia/Reperfusion. Invest Ophthalmol Vis Sci. 2023;64(14):42. doi:10.1167/iovs.64.14.42
4. Cvitkovic K, Sesar A, Sesar I, et al. Concentrations of Selected Cytokines and Vascular Endothelial Growth Factor in Aqueous Humor and Serum of Diabetic Patients. Semin Ophthalmol. 2020;35(2):126-133. doi:10.1080/08820538.2020.1755320
5. Shyam M, Sidharth S, Veronica A, et al. Diabetic retinopathy: a comprehensive review of pathophysiology and emerging treatments. Mol Biol Rep. 2025;52(1):380. Published 2025 Apr 10. doi:10.1007/s11033-025-10490-7
6. Bai Y, Wang X, Qi F, Zuo X, Zou G. Mechanisms of action of retinal microglia in diabetic retinopathy (Review). Int J Mol Med. 2025;56(6):202. doi:10.3892/ijmm.2025.5643
7. Altmann C, Schmidt MHH. The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration. Int J Mol Sci. 2018;19(1):110. Published 2018 Jan 1. doi:10.3390/ijms19010110
8. Liu M, Li H, Yang R, Ji D, Xia X. GSK872 and necrostatin-1 protect retinal ganglion cells against necroptosis through inhibition of RIP1/RIP3/MLKL pathway in glutamate-induced retinal excitotoxic model of glaucoma. J Neuroinflammation. 2022;19(1):262. Published 2022 Oct 26. doi:10.1186/s12974-022