Modulation of Iron-Induced Glucose Metabolic Reprogramming Alleviates Retinal Pigment Epithelial Cell Senescence

This study aimed to investigate whether iron overload induces retinal pigment epithelial (RPE) cell senescence through glucose metabolic reprogramming and to evaluate the therapeutic potential of targeting this metabolic pathway.

We utilized human-induced pluripotent stem cell-derived RPE cells and induced RPE cells, along with mouse models with intravitreal or intraperitoneal injection of ferric ammonium citrate (FAC), to evaluate the effect of iron overload on RPE senescence. Proteomics, targeted metabolomics, reactive oxygen species (ROS) assay kits, JC-1 assay kit, reverse-transcription polymerase chain reaction, SA-β-gal staining, and western blot were used to assess mitochondrial function, ROS, and senescence markers. 2-Deoxy-d-glucose (2-DG), pyruvate kinase M2 inhibitor-1 (PKM2-IN-1), and sodium oxamate (SO) were used to modulate glucose metabolism flux. Flash electroretinography recording was used to assess visual function.

Iron overload triggered significant glucose metabolic reprogramming in RPE cells, characterized by a time-dependent metabolic shift. Early exposure to FAC induced a transient surge in glucose metabolic flux, which elevated mitochondrial ROS production and disrupted mitochondrial homeostasis, ultimately leading to cellular senescence. Importantly, early inhibition of this metabolic surge with 2-DG or PKM2-IN-1 effectively attenuated senescence by reducing ROS levels and preserving mitochondrial function. Conversely, enhancing pyruvate flux with SO exacerbated senescence. The protective effect of 2-DG against iron-induced RPE senescence was further confirmed in a mouse model, where it preserved visual function and reduced senescence markers.

Glucose metabolic reprogramming mediates iron-induced RPE senescence, with transient glucose flux surge driving pathology via ROS-related mitochondrial damage. Targeting glucose metabolism may preserve mitochondria homeostasis and prevent RPE degeneration in age-related macular degeneration.