The redox code of diabetic retinopathy: Decoding metabolic memory, predicting fate, and targeting heterogeneity

Diabetic retinopathy (DR) has traditionally been viewed as a consequence of cumulative oxidative damage. However, the clinical phenomenon of metabolic memory, whereby prior hyperglycemia continues to exert adverse effects despite subsequent glucose normalization, indicates a more complex redox biology. This review advances a paradigm shift from considering reactive species merely as markers of injury to interpreting oxidative signatures as a dynamic, compartment-specific code that records glycemic history, predicts disease trajectory, and enables therapeutic subtyping. We synthesize evidence across multiple redox layers, including protein oxidative post-translational modifications such as S-glutathionylation and tyrosine nitration, lipid peroxidation products, mitochondrial DNA damage, and epigenetic rewriting mediated by SET domain-containing lysine methyltransferase 7 (SETD7, also known as SET7/9)-dependent monomethylation of histone H3 lysine 4 (H3K4me1). Persistent failure of mitochondrial quality control and maladaptive chromatin remodeling may stabilize hyperglycemia-induced redox programs after glucose normalization, whereas exosomal signaling may contribute to their intercellular propagation. In this context, metabolic memory refers to the durable yet potentially modifiable maintenance of these molecular programs rather than absolute biological irreversibility. Moving beyond the failure of generic antioxidant approaches, we introduce a clinical taxonomy of redox subphenotypes, glutathione-deficient, lipid-peroxidation-dominant, mitochondrial reactive oxygen species (ROS)-driven, and epigenetic redox-lock, each linked to candidate, predominantly preclinical, mechanism-matched interventions, including thiol-repleting agents, ferroptosis inhibitors, mitophagy-enhancing or mitochondrial-protective agents, and epigenetic modulators. Finally, we outline an integrated roadmap combining single-cell redox profiling, liquid-biopsy multi-omics, and biomarker-enriched clinical trial designs to translate redox signatures into precision management. Decoding the redox code may extend the traditional oxidative stress paradigm by revealing biologically heterogeneous molecular states with distinct therapeutic implications.