Diabetic Retinopathy Rewritten as a Stage-by-Stage Signaling Map

Diabetic retinopathy has long been treated in clinics as a disease of leaky blood vessels, but a new review argues that this framing misses most of the story. Writing in Molecular Biology Reports, a team led by Wen Liu and Xiangdong Chen of the First Hospital of Hunan University of Chinese Medicine maps the condition as a sequence of overlapping signaling failures that begin long before any vessel visibly deteriorates. Their central claim is deceptively simple: the molecular drivers of early retinal damage, mid-stage inflammation and vessel growth, and late-stage scarring are not variations on a single theme but distinct networks that dominate at different stages. That distinction, the authors contend, explains why therapies that work spectacularly in one phase of the disease can fail or even backfire in another.

The review organizes diabetic retinopathy around the retinal neurovascular unit, the tightly coupled assembly of neurons, glial Müller cells, endothelial cells, pericytes and immune cells that keeps the retina supplied and its blood-retinal barrier intact. In the earliest phase, chronic hyperglycemia inflicts damage through oxidative stress, disturbed lipid metabolism and mitochondrial dysfunction. The mitochondria of retinal cells are particularly vulnerable: damaged mitochondrial DNA persists even after glucose control improves, a phenomenon the field calls metabolic memory. Studies cited in the review show that impaired removal of damaged mitochondria and weakened Nrf2-mediated antioxidant defenses allow this early injury to accumulate silently, weakening the neurovascular unit before any clinically apparent vascular change appears on an ophthalmologist’s chart.

As damage accumulates, the disease shifts into an inflammatory phase driven by a cast of signaling molecules that the review treats as a coordinated network rather than isolated culprits. Nuclear factor kappa B, high-mobility group box 1, Toll-like receptor 4, the receptor for advanced glycation end products, the cyclic GMP–AMP synthase–stimulator of interferon genes pathway, and the NOD-like receptor protein 3 inflammasome together amplify inflammation, promote leukostasis—the sticking of white blood cells to retinal vessel walls—and erode the blood-retinal barrier. Recent work highlighted in the review shows that cGAS/STING activation drives endothelial cell senescence in early disease and that STING-mediated immune activation in microglia worsens neurovascular unit damage. The NLRP3 inflammasome, meanwhile, triggers pyroptosis, an inflammatory form of cell death that further dismantles retinal endothelium.

Once enough capillaries have been lost, the retina becomes hypoxic, and the disease pivots again. Hypoxia-inducible factor 1 alpha and vascular endothelial growth factor signaling surge, driving the neovascularization that defines proliferative diabetic retinopathy. But the review emphasizes that VEGF is only one node in a much larger web. Angiopoietin-2, Wnt/beta-catenin, phosphoinositide 3-kinase/protein kinase B, semaphorin 4D, and endothelial metabolic reprogramming all sustain vessel leakage and abnormal growth. Hypoxic Müller cells secrete VEGF that induces matrix metalloproteinase activity in endothelial cells, while the HIF1α-PFKFB3 pathway rewires endothelial metabolism toward glycolysis to support proliferation. A 2024 study in Nature Communications even links protein O-GlcNAcylation to Hippo signaling as a driver of vascular dysfunction, illustrating how metabolic and mechanical pathways converge.

In advanced disease, the review identifies a final molecular pivot: the angio-fibrotic switch. Transforming Growth Factor Beta, Yes-associated protein and transcriptional coactivator with PDZ-binding motif pathways, and related signaling drive extracellular matrix deposition, fibrovascular membrane formation and traction on the retina. Connective tissue growth factor rises as VEGF falls, and endothelial cells undergo endothelial-mesenchymal transition, morphing into matrix-producing cells. Single-cell transcriptomic studies of fibrovascular membranes reveal unexpected participants, including microglia and the matrix protein AEBP1, suggesting that the scarring phase recruits immune and stromal cells in ways that earlier bulk analyses missed. This stage is what ultimately detaches the retina and causes irreversible vision loss, yet it remains the least pharmacologically addressed.

Against this mechanistic backdrop, the review evaluates the therapeutic landscape with unusual candor. Systemic metabolic control remains the single most powerful early intervention: long-term follow-up from the DCCT/EDIC trial showed durable reductions in retinopathy progression with intensive diabetes therapy. Fenofibrate, a lipid-lowering agent, has shown the most promise among drugs tested for early-stage disease, reducing the need for laser treatment in the FIELD study and slowing progression in the ACCORD trial. Anti-vascular endothelial growth factor therapy, including aflibercept, ranibizumab, bevacizumab and the bispecific antibody faricimab, remains the standard for severe vascular complications, with newer delivery systems such as the ranibizumab port delivery system extending dosing intervals. Corticosteroid implants offer alternatives for persistent macular edema.

Yet the review is blunt about the limits of current approaches. Anti-inflammatory, neuroprotective, anti-fibrotic, gene-based and multi-target strategies are promising in preclinical models but face significant barriers in delivery, safety, model-to-human translation and weak biomarker validation. Sustained intraocular VEGF neutralization, for instance, has been associated with retinal neurodegeneration in diabetic mouse models, raising the possibility that complete VEGF suppression carries its own risks. Gene therapy approaches such as subretinal delivery of RGX-314, tested in neovascular age-related macular degeneration, are being explored for diabetic retinopathy but remain early. The authors call for improved classification of molecules and clinically significant early endpoints to guide targeted therapy, noting that many candidate biomarkers have not been validated in prospective studies.

What makes the review notable is its insistence on pathway crosstalk and feedback loops rather than linear causation. NF-κB, for example, restricts inflammasome activation by promoting the elimination of damaged mitochondria, meaning that blocking NF-κB indiscriminately could paradoxically worsen inflammation. STAT3 activation in endothelial cells increases vascular leakage by downregulating tight junction proteins, but STAT3 activation in microglia increases pericyte apoptosis through a different signaling route, and STAT3 activation in circulating myeloid cells contributes to microvascular dysfunction through yet another mechanism. The same transcription factor, in other words, plays different pathogenic roles depending on which retinal cell type it inhabits—a level of specificity that the review argues must inform any serious therapeutic strategy.

The authors also distinguish carefully between clinical evidence and non-clinical studies, a distinction that matters enormously in a field where rodent models have repeatedly produced therapies that failed in human trials. The PKC beta inhibitor ruboxistaurin, for example, showed promise in phase 3 studies for vision loss but never achieved widespread adoption. The review calls for studies at all stages of the disease, arguing that early intervention targeting mitochondrial dysfunction or oxidative stress may prevent the downstream cascades that currently require invasive intraocular injections. Whether the field can translate this stage-by-stage signaling map into clinically deployable biomarkers and stage-appropriate treatments remains the defining question, but the review offers a framework that could finally match the right drug to the right phase of a disease that has stubbornly resisted one-size-fits-all solutions.

Subject of Research: Stage-dependent signaling networks and therapeutic strategies in diabetic retinopathy: from neurovascular dysfunction to angiogenesis and fibrosis

Article Title: Stage-dependent signaling networks and therapeutic strategies in diabetic retinopathy: from neurovascular dysfunction to angiogenesis and fibrosis

Article References: Liu, W., Wang, D., Wu, P., Peng, Z., Liu, Z., & Chen, X. (2026). Stage-dependent signaling networks and therapeutic strategies in diabetic retinopathy: from neurovascular dysfunction to angiogenesis and fibrosis. Molecular Biology Reports, 53(1), Article 1741. https://doi.org/10.1007/s11033-026-12925-1

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12925-1

Keywords: Stage-dependent, signaling, networks, therapeutic, strategies, diabetic, retinopathy, neurovascular, dysfunction, angiogenesis, fibrosis, scientific research