Blockage of SUMO E1 enzyme inhibits ocular lens fibrosis by mediating SMAD4 SUMOylation

The ocular lens serves as an exemplary biological model for investigating mechanisms of fibrotic disease, particularly through its well-characterized epithelial-mesenchymal transition (EMT) process. In lens capsular fibrosis, lens epithelial cells (LECs) undergo phenotypic transformation mediated by the dysregulation of a complex signaling network. While multiple interconnected pathways have been implicated in this pathogenic process, current therapeutic strategies for anterior subcapsular cataract and postoperative capsular opacification remain predominantly surgical, underscoring the urgent need for targeted pharmacological interventions. SUMOylation, an essential post-translational modification system, orchestrates critical cellular processes, including gene expression, genome integrity, and cell cycle progression. Emerging evidence positions SUMOylation as a critical regulator of EMT in both fibrotic disorders and oncogenesis. Building on these insights, we hypothesized that SUMO-mediated post-transitional modifications may drive LEC transdifferentiation in lens fibrotic pathologies. Our experimental findings demonstrated that elevated global SUMOylation (SUMO1/2/3 conjugates) in human anterior subcapsular cataract specimens correlated with fibrotic progression. Sole SUMO isoform deficiency partially mitigated TGFβ₂-driven EMT and injury-induced anterior subcapsular cataract. SUMO E1 overexpression enhanced LEC proliferative capacity, migration potential, and EMT progression. Pharmacological SUMO E1 inhibition (ML792) suppressed TGFβ₂-induced SMAD4 SUMOylation, nuclear translocation, a critical TGFβ/SMAD signaling event. ML792 also eliminated TGFβ₂-induced LEC EMT and experimental anterior subcapsular cataract. Our results establish SMAD4 SUMOylation as a pivotal molecular switch in lens fibrosis pathogenesis. Employing inhibitory drugs of SUMO conjugation in the years to come has the potential to be a novel therapeutic strategy for fibrotic cataracts.