Oxidative stress is one of the causative factors in progression and etiology of agerelated cataract. Peroxiredoxin 6 (Prdx6), a savior for cells from internal or external environmental stresses, plays a role in cellular signaling by detoxifying reactive oxygen species (ROS) and thereby controlling gene regulation. Using targeted inactivation of the Prdx6 gene, we show that Prdx6-deficient lens epithelial cells (LECs) are more vulnerable to UV-triggered cell death, a major cause of skin disorders including cataractogenesis, and these cells display abnormal protein profiles. PRDX6-depleted LECs showed phenotypic changes and formed lentoid body, a characteristic of terminal cell differentiation and epithelial-mesenchymal transition. Prdx6 Ϫ/Ϫ LECs exposed to UV-B showed higher ROS expression and were prone to apoptosis compared with wild-type LECs, underscoring a protective role for Prdx6. Comparative proteomic analysis using fluorescence-based difference gel electrophoresis along with mass spectrometry and database searching revealed a total of 13 proteins that were differentially expressed in Prdx6 Ϫ/Ϫ cells. Six proteins were upregulated, whereas expression of seven proteins was decreased compared with Prdx6LECs. Among the cytoskeleton-associated proteins that were highly expressed in Prdx6-deficient LECs was tropomyosin (Tm)2. Protein blot and real-time PCR validated dramatic increase of Tm2 and Tm1␣ expression in these cells. Importantly, Prdx6 ϩ/ϩ LECs showed a similar pattern of Tm2 protein expression after transforming growth factor (TGF)- or H2O2 treatment. An extrinsic supply of PRDX6 could restore Tm2 expression, demonstrating that PRDX6 may attenuate adverse signaling in cells and thereby maintain cellular homeostasis. Exploring redox-proteomics (Prdx6 Ϫ/Ϫ ) and characterization and identification of abnormally expressed proteins and their attenuation by PRDX6 delivery should provide a basis for development of novel therapeutic interventions to postpone ROS-mediated abnormal signaling deleterious to cells or tissues.peroxiredoxin; oxidative stress; proteomics; tropomyosin OXIDATIVE STRESS has been identified as one of the major causes of age-related diseases, including cataracts (1, 45, 62, 74 -76, 82). Oxidative stress-induced etiology and progression of diseases may result either from diminished natural antioxidants such as catalase, glutathione peroxidase, and peroxiredoxins (PRDXs) due to aging or from increased generation of reactive oxygen species (ROS) by exposure to environmental factors, X-rays, chemicals, toxins, and ultraviolet (UV) radiation. Environmental stressors such as these have been heavily implicated in the etiology and progression of several diseases by inducing ROS-mediated oxidative stress.UV radiation exposure induces several complex sets of acute or chronic responses that can lead to initiation of diseases through overproduction of ROS. ROS modify cellular signaling. Modulation of signal transduction pathways includes changes in gene expression (18). However, investigation...