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Loss of the cytoprotective protein peroxiredoxin 6 (Prdx6) in cells that are aging or under oxidative stress is known to be linked to the pathobiology of many age-related diseases. However, the mechanism by which Prdx6 activity goes awry is largely unknown. Using Prdx6-deficient (Prdx6−/−) cells as a model for aging or redox active cells, human/mouse lens epithelial cells (LECs) facing oxidative stress and aging lenses, we found a significant increase in the levels of small ubiquitin-like modifier (Sumo)1 conjugates. These cells displayed increased levels of Sumo1 and reduced the expression of Prdx6. Specifically, we observed that Prdx6 is a target for aberrant sumoylation signaling, and that Sumo1 modification reduces its cellular abundance. LECs overexpressing Sumo1 showed reduced expression and activity of Prdx6 and its transactivator specificity protein 1 (Sp1), mRNA and protein with increased levels of reactive oxygen species; those cells were vulnerable to oxidative stress-induced cell death. A significant reduction in Prdx6, Sp1 protein and mRNA expression was observed in redox active Prdx6−/− cells and in aging lenses/LECs. The reduction was correlated with increased expression of Sumo1 and enrichment of the inactive form (dimeric) of Sumo-specific protease (Senp)1. Experiments with Sumo1-fused Prdx6 and Prdx6 promoter-linked to chloramphenicol acetyltransferase reporter gene constructs indicated that Sumo1 dysregulated Prdx6 activity by reducing its abundance and attenuating its transcription; in contrast, the delivery of Senp1 or Prdx6 reversed the process. The data show that reactive oxygen species-evoked aberrant sumoylation signaling affects Prdx6 activity by reducing Prdx6 abundance, as well as transcription. The findings of the present study may provide a foundation for a strategy to repair deleterious oxidative signaling generated by a reduced activity of Prdx6.Herein we showed for the first time that loss of antioxidant protein Prdx6 leads to oxidative stress-induced aberrant Sumoylation signaling during aging, and that Prdx6 is a target for Sumo1 conjugation, and Sumoylation reduces its cellular abundance and activity, leaving lens epithelial cells highly vulnerable to oxidative insults. Conversely, Prdx6 physiological expression attenuates oxidative stress-evoked aberrant Sumoylation-mediated death pathways.