Lactylation-driven FTO-mediated m6A modification of CDK2 aggravates diabetic microvascular anomalies

Chen, X.; Sun, R.-X.; Wang, J.-N.; Zhang, Y.-R.; Qin, B.; Zhang, Y.-C.; Dai, Y.-X.; Zhu, H.-J.; Wang, Y.; Zhao, J.-X.; Zhang, W.-W.; Ji, J.; Yuan, S.-T.; Shen, Q.-D.; Liu, Q.-H.

doi:10.1101/2023.05.19.541470

bioRxiv · 10.1101/2023.05.19.541470

Lactylation-driven FTO-mediated m6A modification of CDK2 aggravates diabetic microvascular anomalies

Chen, X.·Sun, R.-X.·Wang, J.-N.·Zhang, Y.-R.·Qin, B.·Zhang, Y.-C.·Dai, Y.-X.·Zhu, H.-J.·Wang, Y.·Zhao, J.-X.·Zhang, W.-W.·Ji, J.·Yuan, S.-T.·Shen, Q.-D.·Liu, Q.-H.

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Abstract

Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. FTO is an N6-methyladenosine (m6A) demethylase that participates in various biological events, while its role in DR remains elusive. Herein, we detected elevated FTO expression in retinal proliferative membranes of DR patients. FTO promoted endothelial cell (EC) cell cycle progression and tip cell formation to facilitate angiogenesis in vitro, in mice and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetic microvascular leakage, and mediated EC-microglia interactions to induce retinal inflammation and neurodegeneration in vivo and in vitro. Mechanistically, FTO affected EC features via modulating CDK2 mRNA stability in an m6A-YTHDF2-dependent manner. FTO up-regulation under diabetic conditions was driven by lactate mediated histone lactylation. FB23-2, an inhibitor to FTOs m6A demethylase activity, suppressed angiogenic phenotypes in vivo and in vitro. Noteworthy, we developed a nanoplatform encapsulating FB23-2 for systemic administration, and confirmed its targeting and therapeutic efficiencies in mice. Collectively, our study demonstrated that FTO coordinates EC biology and retinal homeostasis in DR, providing a promising nanotherapeutic approach for DR.

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Chen, X., Sun, R.-X., Wang, J.-N., Zhang, Y.-R., Qin, B., Zhang, Y.-C., Dai, Y.-X., Zhu, H.-J., Wang, Y., Zhao, J.-X., Zhang, W.-W., Ji, J., Yuan, S.-T., Shen, Q.-D., Liu, Q.-H.. 2023-05-19. Lactylation-driven FTO-mediated m6A modification of CDK2 aggravates diabetic microvascular anomalies. https://doi.org/10.1101/2023.05.19.541470

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