The role of ubiquitination and deubiquitination modifications in diabetic retinopathy

Diabetic retinopathy (DR), the most prevalent microvascular complication of diabetes, has emerged as a leading cause of blindness in adults aged 20-75 years worldwide. Its progression is driven by inflammation, oxidative stress, and pathological angiogenesis. Ubiquitination, a fundamental post-translational modification in eukaryotes, controls protein fate through the coordinated actions of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). This machinery participates broadly in cell cycle control and signal transduction, and its dysregulation can destabilize cellular homeostasis. In DR, ubiquitination markedly shapes disease development by modulating an array of retinal processes: ferroptosis, oxidative stress, inflammatory cascades, microglial activation, angiogenesis, neuronal injury, and blood-retinal barrier integrity. Preclinical studies have demonstrated the therapeutic promise of targeting deubiquitinating enzymes, ubiquitin ligases, ubiquitination-related signaling pathways, and the ubiquitin-proteasome system. This review delineates the contributions of ubiquitination to the initiation and progression of DR, examines the underlying regulatory mechanisms, and identifies actionable targets, thereby furnishing a mechanistic rationale and future directions for ubiquitination-oriented therapy in DR.