The research, led by Yingying Zhu, Chun Jiang, Xiuhui He, Xiang Gao, and corresponding author Zhengxuan Jiang of the Department of Ophthalmology at The Second Affiliated Hospital of Anhui Medical University, describes a previously underappreciated signaling chain that connects the metabolic chaos of diabetes to the physical collapse of the retinal endothelial barrier. At the heart of the discovery is histone lactylation, a relatively recently identified epigenetic mark in which lactate-derived lactyl groups are chemically attached to lysine residues on histone tails. Rather than being an inert byproduct of metabolism, lactate in this context acts as a signaling molecule that reshapes which genes are switched on inside retinal blood vessel cells.

To dissect the mechanism, the team assembled evidence from multiple complementary systems. They examined human epiretinal membranes and fibrovascular membranes obtained from patients with proliferative diabetic retinopathy, retinal tissue from diabetic rats, and retinal endothelial cells grown under diabetic-like conditions. Across all of these models, a consistent pattern emerged: where lactate accumulated, protein lactylation rose, and one particular mark—lactylation at lysine 9 of histone H3, abbreviated H3K9la—stood out as prominently elevated under diabetic conditions. This convergence across human tissue, animal models, and cultured cells gave the finding a robustness that single-model studies often lack.

The critical question was what H3K9 lactylation actually does inside these endothelial cells. Histone modifications of this kind generally work by altering the physical state of chromatin, the complex of DNA and protein that packages the genome. When specific histone residues are acetylated or lactylated, the chromatin at nearby genes tends to loosen, granting the transcriptional machinery access and boosting gene expression. The researchers found that lactate-driven H3K9la became enriched at the promoter region of the PTK2 gene, which encodes focal adhesion kinase, a well-known regulator of cell adhesion, migration, and survival. With the promoter epigenetically opened up, PTK2 transcription increased, and levels of the phosphorylated, active form of the kinase climbed in parallel.

From there, the story moves from the nucleus to the cytoskeleton. Activated PTK2 was found to associate with FMNL2, a formin-family protein that governs the assembly of actin filaments, and this association was linked to increased tyrosine phosphorylation of FMNL2 itself. The consequence was a cascade of cytoskeletal remodeling inside the endothelial cells: the internal scaffolding of the cells reorganized in a way that destabilized VE-cadherin, the adhesive molecule that stitching neighboring endothelial cells together at adherens junctions. When VE-cadherin junctions falter, the endothelial sheet loses its seals, permeability rises, and fluid and proteins leak across the barrier. In the retina, that leakage translates directly into macular edema and progressive vision impairment.

What makes this axis scientifically compelling is that it forges a direct line from metabolism to cell structure through epigenetics. Diabetic tissue is known to be lactate-rich, a product of altered glucose metabolism and hypoxic stress. The study shows that this excess lactate does not merely fuel inflammation or oxidative damage indirectly; it physically marks the chromatin of barrier-regulating genes, amplifies a kinase–formin signaling module, and dismantles the junctions that hold the retinal vasculature together. In effect, a metabolic byproduct of diabetes becomes an epigenetic instruction that tells blood vessel cells to let go of each other.

Just as importantly, the research demonstrates that the damage is not irreversible in experimental settings. The team showed that pharmacologically reducing lactate production, inhibiting the catalytic activity of CBP/p300—the histone acetyltransferase enzymes responsible for writing lactylation marks—blocking PTK2 activity, or knocking down FMNL2 all attenuated endothelial barrier defects and reduced retinal vascular leakage. Each of these interventions targets a different rung on the same ladder, and the fact that several independent points of disruption produce protective effects strengthens the causal interpretation of the pathway and opens multiple potential angles for therapy.

The therapeutic implications are considerable. Existing treatments for diabetic retinopathy, such as anti-VEGF injections and laser photocoagulation, address downstream consequences of vascular dysfunction rather than the metabolic and epigenetic drivers of barrier failure. If the lactate–H3K9la–PTK2–FMNL2 axis can be safely modulated in patients—for example, by limiting lactate accumulation, tuning histone lactylation, or inhibiting focal adhesion kinase signaling locally in the eye—clinicians might one day intervene earlier in the disease process, before irreversible vascular damage takes hold. PTK2 inhibitors already exist in oncology research, and CBP/p300 catalytic inhibitors are under active investigation in multiple fields, meaning that repurposing strategies could accelerate translation.

The study also adds to a fast-growing body of literature on lactylation as a regulatory modification. Since histone lactylation was first described as a link between cellular metabolism and gene regulation, researchers have implicated it in macrophage polarization, tumor biology, fibrosis, and neural inflammation. The new work extends this framework to the vascular endothelium of the eye, suggesting that lactylation may be a general mechanism by which metabolically stressed tissues lose barrier integrity. Given that barrier failure is central to conditions ranging from sepsis to diabetic kidney disease, the conceptual reach of these findings may extend well beyond ophthalmology.

Caveats remain, as they always do at this stage of research. The pharmacological interventions were tested in experimental and preclinical systems, and the leap from rat retinas and cultured endothelial cells to human therapy will require careful validation, dosing studies, and safety assessment. Human tissue samples from proliferative diabetic retinopathy show the molecular signature, but they represent an advanced stage of disease; whether earlier interventions along this axis prevent progression is a question for future longitudinal work. Still, the identification of a defined metabolic–epigenetic–signaling pathway underlying inner blood–retinal barrier breakdown represents a genuine conceptual advance, one that reframes diabetic retinopathy not simply as a disease of damaged vessels, but as a disease of miswritten chromatin in the cells that guard the eye.

Subject of Research: Lactate-induced H3K9 histone lactylation disrupting the inner blood–retinal barrier via the PTK2–FMNL2 axis in diabetic retinopathy

Article Title: Lactate-induced H3K9 lactylation disrupts the inner blood–retinal barrier by activating the PTK2–FMNL2 axis in diabetic retinopathy

Article References: Zhu, Y., Jiang, C., He, X., Gao, X., & Jiang, Z. (2026). Lactate-induced H3K9 lactylation disrupts the inner blood–retinal barrier by activating the PTK2–FMNL2 axis in diabetic retinopathy. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06448-y

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06448-y

Keywords: diabetic retinopathy, inner blood–retinal barrier, histone lactylation, H3K9la, lactate, PTK2, FMNL2, VE-cadherin, endothelial permeability, focal adhesion signaling, epigenetics, retinal vascular leakage