MicroRNAs (miRNAs) are emerging as important regulators of neurodegenerative diseases. However, research into ocular intracellular miRNAs, though possessing great potential to uncover novel and valuable therapeutic targets for glaucoma, is only at an early stage. Here we show that expression levels of miR-211 were significantly induced in aqueous humor (AH) samples from patients with glaucoma when compared to normal AH samples. Notably, oxidative stress-elicited miR-211 potentiated high pressure-induced retinal ganglion cells (RGCs) death by impairing ERK activation but enhancing P38 activation, an effect mediated by direct downregulation of fibroblast growth factor receptor substrate 2 (Frs2) signaling pathway in a sequence complementarity-dependent fashion. In support of the concept of a fundamental connection between miR-211 upregulation and augmented pressure-induced cell death in RGCs, we showed that ectopic expression of the exogenous FRS2 was sufficient to neutralize the miR-211-induced decrease in the cell viability and significantly improved miR-211-inhibited cell survival, in high pressure-challenged RGC-5 cells. Together, our findings show that miR-211 negatively modulates cell survival programs upon high pressure challenge by regulating Frs2 signaling, and they define roles for miR-211/Frs2 cascade in a regulatory feedback loop that mediates the pathogenesis of glaucoma. (C) 2018 Elsevier Inc. All rights reserved.