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Objective To investigate the protective effect of pyroptosis and anti-Caspase-1 treatment on retinal ganglion cells (RGCs) in rats with acute ocular hypertension. Methods Forty-two SPF male SD rats were randomly divided into normal control group, acute ocular hypertension model group and VX-765 (Caspase-1 inhibitor) intervention group, with the right eye as the experimental eye. Acute ocular hypertension was inflicted by anterior chamber irrigation with normal saline in the model group and intervention group. The rats in the intervention group were further given 4 μL VX-765 (200 μmol/L) solution by intravitreal injection on the modeling day and the next day, and those of the model group were injected with equal volume of normal saline in vitreous cavity at the same time. No such treatment was performed on the rats from the control group. All rats were killed at the seventh day after modeling. Retinal morphology and the density of RGCs were observed by HE staining. The survival of RGCs and average absorbance of retina were observed by immunohistochemical assay. The mRNA levels of Caspase-1, gsdmd, IL-1b and IL-18 were detected by real-time fluorescence quantitative PCR. The protein expression of Caspase 1-p20, gsdmd-n, IL-1b and IL-18 were detected by Western blotting. Results The retinal thickness was 164.53±1.04 μm in the model group, which was significantly thinner than that in the normal control group (181.44±5.13 μm) and the intervention group (173.15±2.15 μm). The density of RGCs was (332.87±16.37)/mm2 in the model group, obviously lower than that in the normal control group and the intervention group. The average absorbance of retina was 0.443±0.014 in the model group, statistically lower than in the normal control group (0.517±0.015) and the intervention group (0.492±0.006). The differences were statistically significant in above values (P < 0.05). The mRNA relative expression levels of IL-1b and IL-18 were significantly higher in the model group than the control group and intervention group (P < 0.05). The protein levels of Caspase1-p20, gsdmd-n, IL-1b and IL-18 were remarkably higher in the model group than the other 2 groups (P < 0.05). Conclusion Acute ocular hypertendion exposure enhances the expression of the molecules in Caspase-1-dependent pyropotosis pathway. So, inhibiting Caspase-1 activity can reduce the severity of retinal injury, protect RGCs effectively, and reduce RGCs death.