Crosstalk between estrogen signaling and Fas-mediated apoptosis determines neuronal resilience after menopause

Age-associated estrogens decline is increasingly recognized as a systemic driver of neurodegeneration, yet the mechanisms by which estrogen deficiency alters neuronal resilience remain incompletely understood. Here, we investigated how mimicking age-related endocrine decline influences the susceptibility of retinal neurons to ischemic stress and whether simultaneous targeting of survival and apoptotic pathways restores neuronal resilience. Using a mouse model of surgical menopause (total N = 62 divided into groups containing 4-6 specimen), we demonstrate that estrogen deficiency markedly exacerbates retinal ganglion cell (RGC) loss by approximately 60% and severely impairs functional recovery following ischemia-reperfusion injury. Pharmacological modulation revealed that selective estrogen receptor signaling or Fas pathway inhibition alone provided partial neuroprotection. However, combined treatment with the selective estrogen receptor modulator Raloxifene and the Fas receptor antagonist KP7-6 produced a powerful synergistic effect, limiting RGC somatic loss to a mere 18% and restoring stratified retinal function to near-physiological levels in both ovariectomized and non-ovariectomized animals. Ex vivo retinal explants (N = 15) confirmed that dual pathway modulation drives a 2-fold increase in neuronal survival and significantly limits cytotoxicity, supporting a direct cellular mechanism. These findings identify endocrine aging as a modifiable driver of neuronal vulnerability and demonstrate that simultaneous targeting of estrogen-dependent survival signaling, and Fas-mediated apoptosis can restore a youthful neuroprotective phenotype. Our results establish convergent hormonal and apoptotic pathways as one of regulators of neuronal resilience during aging and suggest a combinatorial therapeutic strategy for age-related neurodegenerative disorders.