L-Threonic Acid Inhibits Pathological Retinal Neovascularization by Modulation of CCL3–CCR5 Signaling Pathway

Purpose: Based on the integrated metabolomics data of serum and vitreous humor from diabetic retinopathy, this study aimed to elucidate the inhibitory effects and underlying mechanisms of L-threonic acid (L-ThA) on retinal neovascularization. Methods: Cross-tissue metabolomic analysis identified consistently altered metabolites in both biofluids. Candidates negatively associated with proliferative diabetic retinopathy (PDR) progression were then selected through mass spectrometry analysis and disease risk assessment. To validate the inhibitory effects of these metabolites on retinal neovascularization, an oxygen-induced retinopathy (OIR) mouse model was used, and compounds were delivered intravitreally. The downstream signaling mechanisms of these metabolites were further elucidated using transcriptome sequencing, western blotting, co-culture assays, and other complementary molecular techniques. Results: Intersection analysis of differential metabolites in serum and vitreous humor from patients with PDR revealed that L-ThA was significantly downregulated in both biofluids. The reduction in L-ThA levels was associated with disease progression. In a mouse model of OIR, intravitreal injection of L-ThA markedly reduced the retinal neovascular area from 12.34% to 1.67%, demonstrating potent anti-angiogenic effects approaching the efficacy of those anti-vascular endothelial growth factor therapies. Transcriptomic and molecular analyses further elucidated that L-ThA suppresses retinal neovascularization by inhibiting the expression and secretion of C-C motif chemokine ligand 3 (CCL3) in retinal microglia/macrophages, thereby reducing its interaction with the CCR5 receptor on vascular endothelial cells. Conclusions: Cross-tissue metabolomics revealed L-ThA as a metabolite consistently downregulated in PDR; functional studies suggest it possesses anti-angiogenic effects by modulation of CCL3-CCR5 signaling, representing a potential biomarker and therapeutic target for PDR.