Corneal Endothelial Injury Repair: Cellular Mechanisms, Molecular Regulation, and Therapeutic Strategies

Background/Objectives: Corneal endothelial cells (CECs) maintain corneal transparency through barrier and pump functions but have minimal proliferative activity in the adult human eye. After injury, repair relies mainly on migration, spreading, and enlargement of surviving cells. Functional recovery may nevertheless fail because of endothelial-to-mesenchymal transition, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and apoptosis. This review summarizes the mechanisms of corneal endothelial injury repair, with emphasis on pharmacologically relevant signaling pathways, post-translational modifications (PTMs), and organelle homeostasis. Methods: This narrative review synthesizes experimental and clinical evidence on corneal endothelial injury repair, with emphasis on cellular signaling, PTMs, organelle homeostasis, and emerging therapeutic strategies. Relevant literature was identified through PubMed searches using combinations of terms related to corneal endothelial cells, endothelial repair, wound healing, Fuchs endothelial corneal dystrophy, signaling pathways, PTMs, organelle homeostasis, cell therapy, and gene- or RNA-based therapy; reference lists of key publications were also screened. Literature was selected according to relevance to the mechanistic and translational scope of the review, with attention to evidence from adult human tissue, cultured human CECs, animal models, disease-specific models, and clinical studies. Results: RhoA/ROCK, PI3K/Akt, Wnt/β-catenin, FGF, and TGF-β pathways regulate migration, survival, proliferation, and phenotypic stability. Phosphorylation-dependent cytoskeletal regulation and the SENP1–PAX6 SUMOylation axis have relatively direct links to repair, whereas microtubule modifications and methylation remain less well defined. Mitochondrial bioenergetics, redox balance, and ER proteostasis are important for CEC survival and functional maintenance, while the roles of Golgi trafficking and primary cilia require further study. Therapeutic strategies include endothelial keratoplasty, ROCK inhibitor-assisted Descemet stripping only (DSO), cultured CEC transplantation, stem-cell-derived endothelial cell therapy, pharmacological interventions, and gene- and RNA-based therapies. Conclusions: Current evidence supports matching treatment to residual endothelial reserve, disease stage, and the dominant disease mechanism. Established endothelial replacement remains central for advanced failure, whereas ROCK inhibitor-assisted DSO provides a donor-sparing option in selected eyes with sufficient residual endothelial reserve. Cell-based therapies have reached clinical or regulatory application, while most PTM-, organelle-, and gene/RNA-directed mechanisms remain at preclinical or early translational stages.