Curcumol targets the FTO/MAFG-AS1 axis to alleviate diabetic retinopathy via epigenetic remodeling and nanodelivery-based microenvironment modulation.

Abstract

Diabetic retinopathy (DR) is a major microvascular complication of diabetes, with its pathogenesis involving metabolic memory, epigenetic dysregulation, and multi-cellular microenvironmental disorders. This study systematically investigates the mechanism by which curcumol ameliorates DR through regulation of the FTO/MAFG-AS1 epigenetic axis and reveals its therapeutic potential in targeting the retinal microenvironment via a nano-delivery system. Experimental results demonstrate that curcumol activates the demethylase activity of FTO, stabilizing the expression of the long non-coding RNA MAFG-AS1, thereby inhibiting high glucose-induced retinal endothelial cell inflammation, migration, and vascular leakage. Single-cell transcriptomic analysis further uncovered the dual role of FTO in DR: On the one hand, it promotes pathological angiogenesis in endothelial cells, while on the other hand, it exerts protective effects through MAFG-AS1-mediated antioxidative and anti-inflammatory functions. Moreover, this study proposes a multidimensional epigenetic regulatory network based on histone lactylation, N6-methyladenosine modification, and DNA methylation, and verifies that curcumol delays DR progression by coordinately modulating these modifications. To overcome the limitations of conventional therapies, this study innovatively designed a macrophage membrane-coated nano-delivery system, significantly enhancing the retinal targeting and bioavailability of curcumol. Finally, the study advocates a paradigm shift from passive treatment to early prevention, proposing a three-tiered intervention strategy that integrates epigenetic biomarkers with artificial intelligence-based risk assessment. These findings not only elucidate the multi-target regulatory mechanisms of curcumol but also provide a theoretical foundation for the development of precision therapies for DR based on epigenetic remodeling and microenvironmental synergistic intervention.