Lycium barbarum leaves ameliorate diabetic retinopathy by regulating MAPK/NF-κB/VEGF signaling axis and gut microbiota-inflammation crosstalk

Abstract Lycium barbarum leaves (LBL), a medicinal and edible plant traditionally used in China, exert proven anti-diabetic effects, however, their potential for ameliorating diabetic retinopathy (DR) remains unclear. We aimed to screen LBL bioactive fractions (LBLBFs) and clarify their underlying mechanisms. LBL fractions were evaluated in high-glucose-injured zebrafish and retinal cells to identify LBLBFs; Ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry analysis identified flavonoids and phenolic acids as the core bioactive components, which guide network pharmacology-based mechanism prediction. In the screening models, LBLBFs significantly reduced oxidative stress and ROS levels. In mice with DR induced by a high-fat/high-sugar diet and streptozotocin, multi-dimensional validation showed that LBLBFs alleviated DR-related inflammation, retinal damage, and aberrant angiogenesis by downregulating the MAPK/NF-κB/VEGF axis. They also regulated gut microbial homeostasis to reduce circulating lipopolysaccharide levels and synergistically inhibit this pathway. In conclusion, LBLBFs improve DR via dual mechanisms, highlighting their potential as multicomponent, multitargeted functional food ingredients suitable for long-term dietary intervention.