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bioRxiv · 10.64898/2026.01.07.697636

YAP activation reverses aging-related visual dysfunction caused by impaired cell-matrix adhesion

Kim, G.·Son, C.·Lee, H. K.·Choi, J.·Lee, S.·Oh, S.·Chae, J.-B.·Park, C.-W.·Kim, C.·Ryu, J.-H.·Jang, J.·Chung, H.
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Abstract

Cellular senescence of retinal pigment epithelium (RPE) cells drives age-related visual decline, particularly in the pathology of age-related macular degeneration (AMD). While genome-wide association studies (GWAS) have identified genetic risk factors underlying AMD, the molecular mechanisms governing RPE senescence remain unclear. Here, single-cell RNA sequencing of young and old mouse RPE revealed dysregulated cell-matrix adhesion as a key feature of senescence, consistent with transcriptional changes in AMD patients. Hydrogel-based experiments confirmed that impaired integrin-mediated adhesion induces RPE senescence. Yes-associated protein 1 (YAP), a crucial mechanotransducer, mediated the protective effects of cell-matrix adhesion, and its activation alone reversed aging phenotypes in senescent RPE cells. Notably, treatment with TRULI, a small-molecule YAP activator, significantly improved visual function in AMD and naturally aged mice. These findings highlight the integrin-YAP mechanotransduction pathway as a fundamental regulator of RPE senescence and a potential therapeutic target for AMD.

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Kim, G., Son, C., Lee, H. K., Choi, J., Lee, S., Oh, S., Chae, J.-B., Park, C.-W., Kim, C., Ryu, J.-H., Jang, J., Chung, H.. 2026-01-08. YAP activation reverses aging-related visual dysfunction caused by impaired cell-matrix adhesion. https://doi.org/10.64898/2026.01.07.697636

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