St6gal1-mediated sialylation protects retinal ganglion cells by restraining microglial phagocytosis.

The death of retinal ganglion cells (RGCs) is a pivotal pathological event that leads to irreversible vision loss following optic nerve injury. RGCs display substantial heterogeneity, with distinct subtypes exhibiting variable resilience to injury, but the mechanisms underlying the intrinsic survival advantage remain to be defined. Here, by analyzing mouse RGC single-cell RNA sequencing datasets, we found that αRGCs expressed markedly higher levels of sialyltransferases, particularly ST6Gal1. In the mouse optic nerve crush (ONC) model, we confirmed that blockade of sialylation significantly reduced αRGC survival. Conversely, overexpression of ST6Gal1 enhanced the survival of intrinsically photosensitive RGCs and other RGCs after ONC, and conferred broad neuroprotection in additional in vivo mouse retinal injury models including I/R and NMDA excitotoxicity. Notably, overexpressing ST6TGal1 promoted optic nerve axon regeneration independent of mTOR signaling activation. Mechanistically, single-cell transcriptomic profiling revealed that ST6Gal1-mediated sialylation potentially facilitated the transition of microglia toward a homeostatic state after injury, thereby attenuating phagocytic clearance of RGCs. Together, these findings uncover a previously unrecognized sialylation-mediated regulatory axis that promotes RGC survival and optic nerve regeneration, offering a neuron-directed strategy to mitigate microglia-driven neurodegeneration.