GHRHR Deficiency Enhances Retinal Ganglion Cell Survival and Visual Functions in Experimental Glaucoma by Inhibiting Ferroptosis

ABSTRACT Glaucoma is a leading cause of irreversible blindness worldwide. One hallmark of glaucoma is the degeneration of retinal ganglion cells (RGCs). In this study, a dual role for growth hormone‐releasing hormone receptor (GHRHR) modulation under glaucoma‐relevant conditions and complementary injury paradigms involving the RGCs is identified. Using acute IOP elevation (retinal ischemia‐reperfusion), chronic ocular hypertension (microbead‐induced), and traumatic axonal injury (optic nerve crush) models, we show that GHRHR deficiency preserves RGC survival and uniquely restores visual functions—contrasting with GHRHR activation, which solely promotes cellular survival. Single‐cell transcriptomic analysis uncovers RGC‐specific alterations in genes associated with ferroptosis, lipid metabolism, oxidative stress, and mitochondrial dynamics. At the mechanistic level, GHRHR deficiency prevents the pathological downregulation of key anti‐ferroptotic mediators GPX4 and FTH1 while suppressing pro‐ferroptotic factors ACSL4 caused by glaucomatous neurodegeneration. This multifaceted regulation attenuated iron accumulation, lipid peroxidation, and reactive oxygen species (ROS) accumulation, effects that are diminished by the ferroptosis inducer RSL3. Notably, in mitochondria damaged primary RGCs, pharmacological GHRHR inhibition replicates these benefits, reducing lipid peroxidation and mitochondrial ROS to bolster RGC survival. Collectively, these findings establish GHRHR inhibition as a potent therapeutic strategy for glaucomatous neurodegeneration, synergistically rescuing both structural and functional integrity of the retina.