Multi‐Omics Reveals STAT1 as a Central Regulator of Oxidative Stress‐Induced Senescence in the Aging Retina

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Abstract
Aging is the dominant risk factor for retinal neurodegeneration, yet the upstream regulators that coordinate senescence‐associated programs across retinal cell types remain incompletely defined. Here we combined bulk RNA‐seq and quantitative proteomics of retinas from naturally aged (24‐month) and young (4‐month) mice to define age‐associated molecular programs and infer upstream regulators. We identified coordinated but imperfect transcript‐protein coupling, with prominent immune and metabolic activation and concomitant repression of visual and structural pathways. Network‐based integration nominated Stat1 as a convergent hub linking oxidative stress, inflammatory signaling, and cell fate regulation. Functionally, STAT1 induction accompanied oxidative stress‐driven senescence in human ARPE‐19 cells; ectopic STAT1 expression was sufficient to elicit senescence‐like transcriptional changes, increase reactive oxygen species, and activate inflammasome‐associated signaling, whereas STAT1 knockdown attenuated TBHP‐induced senescence, reduced p53 and ASC upregulation, and blocked stress‐induced nuclear accumulation of STAT1. Re‐analysis of aging retina single‐cell RNA‐seq data further localized Stat1 expression primarily to horizontal cells and glial populations, while Stat1 target programs were engaged across multiple retinal cell types, consistent with compartmentalized initiation and multicellular propagation of inflammatory aging cues. Together, these data establish STAT1 as a mechanistic driver and cell‐context‐dependent marker of retinal aging, providing a rationale for targeting STAT1‐centered pathways to delay or mitigate age‐related retinal degeneration.

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