| RRC ID |
83874
|
| 著者 |
Fujimoto S, Endo M, Tonomura S, Tsuji F, Haraguchi H, Hasegawa K, Numao T, Izumi A, Tourtas T, Schlötzer-Schrehardt U, Kruse F, Oyama Y, Ikawa M, Jun AS, Koizumi N, Okumura N.
|
| タイトル |
Therapeutic Potential of Emricasan, a Pan-Caspase Inhibitor, in Reducing Cell Death and Extracellular Matrix Accumulation in Fuchs Endothelial Corneal Dystrophy.
|
| ジャーナル |
Cells
|
| Abstract |
Fuchs endothelial corneal dystrophy (FECD) is a progressive disorder characterized by endothelial cell loss and excessive extracellular matrix (ECM) accumulation leading to corneal dysfunction. Emricasan, a pan-caspase inhibitor, was investigated for its therapeutic potential in suppressing these pathological changes. Patient-derived FECD cells and stress-induced cell models were treated with emricasan to assess its effects on apoptosis and ECM production. Caspase-specific knockdown experiments were performed to identify key mediators. Col8a2Q455K/Q455K mice, model mice of early-onset FECD, received twice-daily administration of 0.1% emricasan eye drops from 8 to 28 weeks of age. Endothelial cell density, hexagonality, cell size variation, and guttae area were evaluated by contact specular microscopy, while transcriptomic changes were analyzed via RNA sequencing. Emricasan effectively reduced apoptosis and ECM production in vitro by selectively inhibiting caspase-7 without affecting canonical TGF-β signaling. In vivo, emricasan-treated mice exhibited significantly higher endothelial cell density, improved hexagonality, and reduced variation in cell size compared with controls. Transcriptome analysis revealed distinct gene expression changes in the corneal endothelium following emricasan treatment. These findings suggest that emricasan exerts dual protective effects by inhibiting caspase-7-mediated ECM accumulation and broadly suppressing apoptosis, highlighting its potential as a pharmacological therapy for FECD.
|
| 巻・号 |
14(7)
|
| 公開日 |
2025-3-27
|
| DOI |
10.3390/cells14070498
|
| PII |
cells14070498
|
| PMID |
40214452
|
| PMC |
PMC11988121
|
| MeSH |
Animals
Apoptosis / drug effects
Caspase Inhibitors* / pharmacology
Caspase Inhibitors* / therapeutic use
Cell Death / drug effects
Disease Models, Animal
Extracellular Matrix* / drug effects
Extracellular Matrix* / metabolism
Fuchs' Endothelial Dystrophy* / drug therapy
Fuchs' Endothelial Dystrophy* / genetics
Fuchs' Endothelial Dystrophy* / metabolism
Fuchs' Endothelial Dystrophy* / pathology
Humans
Male
Mice
Mice, Inbred C57BL
|
| IF |
4.366
|
| リソース情報 |
| ヒト・動物細胞 |
293T(RCB2202) |
