The Wnt/StarD7 axis protects retinal ganglion cells from glutamate excitotoxicity by inhibiting ferroptosis.

BACKGROUND

Glutamate (Glu) accumulation-induced excitotoxicity is a major cause of retinal ganglion cell (RGC) death in glaucoma, and the role of ferroptosis, a novel form of cell death, is critical in this process. The aim of this study was to investigate the function and regulatory mechanisms of the lipid transport protein StarD7 in RGC ferroptosis.

METHODS

An N-methyl-D-aspartate (NMDA)-induced retinal excitotoxicity mouse model and a Glu-induced RGC cell model were constructed for experimental investigation. RT‒qPCR and Western blotting were used to assess the expression of related genes and proteins, HE staining was used to assess pathological retinal damage, and kits were used to evaluate ferroptosis-related indicators.

RESULTS

Ferroptosis was involved in NMDA-induced RGC damage in glaucoma mice. StarD7 expression was upregulated in glaucoma, and overexpression of StarD7 decreased the levels of total iron, Fe2+, ROS, and MDA in vitro and in vivo while increasing the expression levels of GSH, GPX4, and xCT, thereby suppressing RGC ferroptosis. Mechanistically, Glu treatment significantly reduced the expression of the Wnt signaling pathway proteins Wnt1 and β-catenin. Activating the Wnt/β-catenin pathway promoted StarD7 expression, which in turn inhibited Glu-induced ferroptosis in mRGCs.

CONCLUSION

The Wnt/β-catenin signaling pathway inhibits Glu-induced RGC ferroptosis by upregulating StarD7 expression, revealing the potential neuroprotective role of StarD7 in glaucoma treatment and providing a scientific basis for the development of new therapeutic strategies.

CLINICAL TRIAL NUMBER: Not applicable.