A peripheral subpopulation of retinal pigment epithelium resists oxidative damage through SERPINE3-mediated caspase-1 inhibition.

Heterogeneous degeneration of the retinal pigment epithelium (RPE) leads to irreversible blindness in diseases associated with macular atrophy. However, the underlying mechanisms of regional RPE degeneration remain poorly understood. To address this gap, this study identified a peripheral RPE subpopulation through spatial, transcriptomic, and functional analyses, thereby contributing to the understanding of the heterogeneity of degenerative RPE cells. Specifically, omics analyses in human and macaque RPE revealed a peripheral RPE cell population with high SERPINE3 expression, while SERPINE3-GFP-knockin mice showed comparable expression patterns. SMART RNA-seq2 analysis further distinguished transcriptomic profiles between GFP+ and GFP- RPE cells. Under oxidative stress, SERPINE3 expression increased, and GFP+ cells exhibited improved survival and reentry into the cell cycle. Notably, genetic studies indicated that SERPINE3 is essential for the oxidative stress resistance of GFP+ cells. Moreover, loss of SERPINE3 resulted in regional RPE degeneration and increased microglial accumulation in aged mice. Mechanistically, proteinase screening and co-IP indicated that SERPINE3 targets caspase-1. Importantly, delivery of SERPINE3 via AAV-Serpine3 partially reduced RPE degeneration in an oxidative damage model. These findings advance the understanding of RPE heterogeneous degeneration and highlight SERPINE3 as a protective factor with therapeutic potential for macular atrophy.