DAPL1 inhibits epithelial-mesenchymal transition of retinal pigment epithelial cells by regulating the TGF-β/MITF pathway

  • Exp Eye Res. 2025 Jun 2:258:110473. doi: 10.1016/j.exer.2025.110473.
Yaqi You  1 ,  Youjia Liu  1 ,  Lijing Huang  1 ,  Wan-Ni Lu  1 ,  Yingxin Zhang  1 ,  Tianyin Nie  1 ,  Meiyu Jing  1 ,  J Fielding Hejtmancik  2 ,  Xingyi Li  3 ,  Ling Hou  4 ,  Xiaoyin Ma  5
Affiliations
  • 1. Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
  • 2. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 3. National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China. Electronic address: [email protected].
  • 4. Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China. Electronic address: [email protected].
  • 5. Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China. Electronic address: [email protected].
PMID: 40466854 DOI: 10.1016/j.exer.2025.110473
Abstract

Epithelial-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is a critical factor in the development of retinopathies, including proliferative vitreoretinopathy (PVR) and age-related macular degeneration (AMD), which are the leading causes of blindness worldwide. Deficiency in DAPL1 can induce RPE-EMT in vivo, and Dapl1 knockout mice (Dapl1 -/-) are prone to PVR, while aged Dapl1 -/- mice display AMD-like pathological features. However, the molecular mechanisms through which DAPL1 regulates RPE-EMT remain largely unknown. Here, using Dapl1 -/- mice and DAPL1 knockdown or overexpression RPE cells, we show that DAPL1 inhibits RPE-EMT by regulating the TGF-β/MITF signaling pathway, a critical signaling pathway/transcription factor in RPE cells. Overexpression of DAPL1 inhibits TGF-β-induced RPE-EMT, while deletion of Dapl1 in mice activates TGF-β signaling, decreases MITF expression, and promotes RPE-EMT under physiological or PVR pathological conditions. Gene therapy demonstrates that transgenic overexpression of MITF in Dapl1 -/- mice inhibits RPE-EMT in vivo and prevents retinal detachment-induced PVR pathological progress, offering hope for future treatment. Similarly, pharmacological therapy with Isoviolanthin, a flavonoid glycoside isolated from traditional medicinal herbs, inhibits TGF-β signaling and increases MITF expression in RPE cells in Dapl1 -/- mice, which then effectively rescues experimental PVR in Dapl1 -/- mice. These results suggest that DAPL1 regulates RPE-EMT at least partial through the TGF-β/MITF pathway and that targeting the TGF-β/MITF pathway could be a potential therapeutic strategy to treat Dapl1 deficiency-induced RPE-EMT-related retinal diseases, instilling hope for the future of retinal disease treatment.

Keywords
DAPL1; EMT; MITF; PVR; RPE; TGF-β signaling.
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