Aging, oxidative stress, and cataracts: Therapeutic prospects and translational insights into peroxiredoxin 6

Selenium-independent peroxiredoxin 6 (Prdx6) is a unique member of the peroxiredoxin family, which protects cells from various stressors by regulating reactive oxygen species (ROS) and maintaining survival signaling. As a multifunctional "moonlighting" protein, Prdx6 exhibits glutathione peroxidase (GPx), acidic calcium-independent phospholipase A2, and lysophosphatidylcholine acyltransferase activities, enabling it to reduce ROS. Loss of Prdx6, owing to dysregulation of its transactivator nuclear factor erythroid 2-related factor 2 or aberrant oxidative post-translational modifications from aging or oxidative stress, disrupts cellular homeostasis and triggers inflammatory or non-inflammatory cell death, including apoptosis and pyroptosis. Similar to GPx4, Prdx6 exhibits selenium-independent peroxidase activity and possesses phospholipid hydroperoxide–reducing GPx activity. A novel function of Prdx6 in facilitating selenium utilization was identified recently; that is, it enhances the expression and activity of selenoproteins, especially GPx4, and prevents ferroptosis. Conversely, Prdx6 deficiency reduces selenoprotein levels and promotes ferroptosis. Nevertheless, the molecular mechanisms through which Prdx6 modulates cell death and survival, particularly under aging and oxidative stress conditions contributing to cataractogenesis, remain unclear. In this review, we summarize the current knowledge of Prdx6 regulation and activity during oxidative stress and aging, highlighting its role in inflammatory and non-inflammatory signaling that contributes to eye lens pathology and cataract formation. Additionally, we discuss natural activators and potential therapeutic strategies targeting Prdx6 to extend eye lens health and delay or prevent cataract development. Overall, we conclude that enhancing Prdx6 activity offers a promising strategy to prevent or reverse age-related cataracts. • Multitasking Prdx6 is vital for controlling gene regulation and lens cell survival. • Prdx6 facilitates selenium utilization to selenoproteins, such as Gpx4. • Prdx6 loss results in Gpx4 expression and activity suppression and cell death. • Prdx6 and Gpx4 are prerequisites for cell survival and -protection. • SFN, metformin, and GA activate Prdx6 via distinct transcription factors. • Metformin or Hyd activates Prdx6 and delays/prevents aging mouse lens opacity • Metformin restores Prdx6 expression by enhancing Nrf2 and Bmal1 binding activity.