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RET inhibition by selpercatinib suppresses TGF-β1-induced epithelial-mesenchymal transition in retinal pigment
Meilan Chen1, Rui Zhao2, Xiaohui Chen3
1The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, China.
Purpose:
The transforming growth factor-β (TGF-β) pathway is a master regulator of epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells, a key process in fibrotic ocular diseases. However, key modulators fine-tuning this pathway in RPE are incompletely characterized. This study investigates the role of the receptor tyrosine kinase RET in TGF-β1-induced RPE-EMT.
Methods:
The role of RET was assessed in vitro using the clinically approved RET inhibitor, Selpercatinib, in RPE cells stimulated with TGF-β1. Outcomes included EMT markers, migration, proliferation, and transcriptional reprogramming. Key downstream signaling effectors Smad3 and ERK were analyzed. In vivo validation was performed in mouse models of TGF-β1-induced EMT and sodium iodate (NaIO3)-induced RPE injury.
Results:
Pharmacological inhibition of RET with Selpercatinib effectively suppressed TGF-β1-induced EMT, migration, proliferation, and associated transcriptional reprogramming in RPE cells. Mechanistically, RET kinase activity was required for the TGF-β1-induced activation of Smad3 and ERK. In mouse models, Selpercatinib treatment attenuated RPE-EMT and preserved retinal structure.
Conclusions:
Our findings establish RET as a critical modulator in the TGF-β signaling pathway in RPE cells and highlight the therapeutic potential of repurposing RET inhibitors for the treatment of fibrotic retinal diseases.
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