Diabetic retinopathy (DR), a progressive neurovascular disorder in diabetic retinas, manifests through interrelated pathological mechanisms including persistent oxidative damage, subclinical inflammation, and metabolic imbalance. Its clinical significance is compounded by an asymptomatic early phase and irreversible progression. Representing the most prevalent cause of preventable sight impairment in economically active age groups, DR constitutes a major public health issue globally [1]. Recent epidemiological studies indicate that diabetes affects approximately 820 million adults globally, with DR prevalence approaching 20 % in this cohort [2,3]. This disease burden underscores the urgent need for improved therapeutic strategies and healthcare resource allocation.

Historically, the medical lens focused tightly on microvascular dysfunction when examining DR. This framing, although partially valid, now seems reductive. Retinal neurodegeneration begins subtly and, in many cases, well before capillary abnormalities are clinically apparent [4,5]. Neuronal compromise often precedes any ophthalmoscopic changes. The pathological cascade involves retinal ganglion cells (RGCs), and other retinal structures, each actively and uniquely contributing to cellular breakdown. On the molecular front, DR originates from persistent hyperglycemia that destabilizes the finely tuned homeostasis of the retina. Excess glucose contributes to reactive oxygen species (ROS) overabundance and a decline in the retina's innate antioxidative properties. This imbalance creates a pro-oxidant microenvironment, where unrelenting oxidative pressure aggravates cellular vulnerability. Damage accumulates. A redox crisis unfolds, setting the stage for structural and functional disintegration [6]. The retina, demanding in energy and densely populated with mitochondria, becomes especially susceptible to this metabolic insult. As oxidative stress intensifies, photoreceptor cells begin to deteriorate. The damage is not confined to these light-sensitive neurons; it propagates along retinal circuits, eroding synaptic integrity and weakening neurovascular coupling. With time, this cascading degeneration impairs not just visual clarity, but the retina's entire capacity to process light into coherent neural signals [7].

Although the centrality of oxidative stress in DR is now well accepted, the precise molecular mechanisms orchestrating RGC injury remain enigmatic. This knowledge gap has hampered the development of effective neuroprotective interventions. Our previous research has identified the antioxidant protein PARK7 (DJ-1) as essential for protecting RGCs from oxidative damage [8]. However, the upstream regulatory circuits that modulate DJ-1 expression in the diabetic retina have remained largely obscure.

While traditional studies have focused heavily on proteomic alterations in DR, a new frontier is rapidly gaining momentum: epigenetic regulation [9,10]. The regulation of genes through epigenetic changes occurs without modifying the DNA sequence. These modifications are crucial in cellular responses to environmental stimuli and are increasingly implicated in chronic disease development [11]. MicroRNAs (miRNAs) regulate gene expression after transcription by attaching to complementary sites on target mRNAs, resulting in mRNA degradation or translation suppression [12,13]. Recent studies have increasingly examined miRNAs’ role in DR, especially their regulation of RPE function, pathological neovascularization, and pericyte integrity [[14], [15], [16], [17]]. Amid this landscape, miRNA-122 has surfaced as a molecule of intrigue. Predominantly known for its hepatocellular abundance and pivotal role in lipid metabolism [18,19], miRNA-122 is now being implicated in extrahepatic pathologies, including DR. Clinical findings have shown that serum levels of miRNA-122 progressively increase with DR severity, rising from healthy individuals to patients with non-proliferative DR [20]. You et al. employed bioinformatics approaches to uncover a regulatory network involving miRNA-122, which appears to be intimately linked to the development of DR; however, the study did not further clarify its expression dynamics or delineate its functional mechanisms in this context [21]. Interestingly, a significant decline in miRNA-122 levels has been observed in the proliferative stage of DR, suggesting a stage-specific regulatory mechanism that has yet to be fully understood [20]. Furthermore, miRNA-122 has been implicated in promoting apoptosis in retinal pigment epithelium cells, indicating its potential contribution to DR development and progression [22]. However, its role and potential molecular mechanism in regulating RGC fate under diabetic conditions has remained an open question.

In this study, we sought to illuminate this underexplored axis. We investigated the effect of miRNA-122-5p on RGCs using a type 1 diabetes mellitus (T1DM) mouse model and a high-glucose cellular paradigm. Under hyperglycemic conditions, miRNA-122-5p expression is markedly elevated, directly leading to repression of DJ-1, amplifying oxidative stress, and promoting RGC apoptosis. Strikingly, silencing miRNA-122-5p restores DJ-1 levels, reestablishes redox equilibrium, preserves mitochondrial integrity, and enhances RGC survival. These findings enhance our comprehension of DR pathogenesis and highlight the miRNA-122/DJ-1 axis as a promising target for neuroprotective therapy in DR.