Retinopathy of prematurity (ROP) is a retinal neovascularization (RNV) disease that is characterized by abnormal blood vessel development in the retina. Importantly, the etiology of ROP remains understudied. We re-analyzed previously published single-cell data and discovered a strong correlation between microglia and RNV diseases, particularly ROP. Subsequently, we found that reactive oxygen species reduced autophagy-dependent protein degradation of absent in melanoma 2 (AIM2) in hypoxic BV2 cells, leading to increased AIM2 protein accumulation. Furthermore, we engineered AIM2 knockout mice and observed that the RNV was significantly reduced compared to wild-type mice. In vitro vascular function assays also demonstrated diminished angiogenic capabilities following AIM2 knockdown in hypoxic BV2 cells. Mechanistically, AIM2 enhanced the M1-type polarization of microglia via the ASC/CASP1/IL-1 beta pathway, resulting in RNV. Notably, the administration of recombinant protein IL-1 beta exacerbated angiogenesis, while its inhibition ameliorated the condition. Taken together, our study provides a novel therapeutic target for ROP and offers insight into the interaction between pyroptosis and autophagy. Under hypoxia, autophagy is impaired, leading to increased AIM2 protein accumulation. AIM2 promotes M1-type activation of BV2 cells and enhances the expression of ASC, CASP1, and IL-1 beta, consequently aggravating angiogenesis. image