| Peroxiredoxin 1 (PRDX1), originally identified as PAG, is a typical 2‑Cys peroxiredoxin that functions both as an antioxidant peroxidase and as a signal transducer for hydrogen peroxide, integrating redox control with growth and stress signaling in mammalian cells. The protein forms obligate homodimers in which each subunit contributes a peroxidatic cysteine in the N‑terminal region and a resolving cysteine in the C‑terminal region; during catalysis, the peroxidatic cysteine reacts with hydrogen peroxide or organic hydroperoxides to form a sulfenic acid intermediate that then forms an intersubunit disulfide bond with the resolving cysteine before reduction by thioredoxin or other thiol-containing donors regenerates the active enzyme. This cycle allows PRDX1 to maintain low steady-state concentrations of hydrogen peroxide under basal conditions, limiting oxidative damage to DNA, proteins, and lipids, while still permitting hydrogen peroxide to act as a second messenger in pathways controlling cell growth, differentiation, and survival. At higher local peroxide fluxes, PRDX1 becomes transiently overoxidized at the peroxidatic cysteine to sulfinic acid, which attenuates its peroxidase activity and shifts the protein toward a chaperone-like state; this oxidation–reduction switching regulates PRDX1’s dual role as a “H₂O₂ safe‑guard” and as a redox sensor that participates in the spatial and temporal shaping of reactive oxygen species signals. PRDX1 also functions as a signal peroxidase that directly transfers oxidative equivalents to specific client proteins via disulfide exchange, as shown for apoptosis signaling kinase 1 (ASK1), where PRDX1 forms a transient mixed disulfide with ASK1 and promotes its oxidation to disulfide‑linked multimers that support downstream p38 MAPK activation, thereby channeling extracellular or intracellular peroxide into defined kinase cascades rather than allowing indiscriminate oxidation of signaling components. In this signaling mode, PRDX1 competes with other cytosolic peroxiredoxins for hydrogen peroxide and exhibits substrate selectivity that helps determine which redox-sensitive pathways are engaged under a given stimulus, linking PRDX1 abundance and oxidation state to the threshold and kinetics of stress-activated MAPK and apoptotic signaling. PRDX1/PAG interacts with the Myc Box II domain of c‑Myc and modulates its transcriptional activity and target gene expression, a connection that places PRDX1 at the intersection of redox control and oncogenic transcription and provides a mechanism by which changes in PRDX1 levels or oxidation state influence cell-cycle progression, proliferation, and transformation. In cancer, PRDX1 is frequently overexpressed and regulates ROS‑dependent pathways that support tumor progression and metastasis, with context-dependent behavior where antioxidant and chaperone functions can either promote survival of transformed cells under oxidative stress or contribute to tumor-suppressive effects through modulation of genome-protective and apoptotic pathways. PRDX1 is widely expressed in human tissues, including erythrocytes, liver, lung, and immune cells, and participates in innate and inflammatory responses by shaping peroxide signals downstream of cytokines and pathogen-associated stimuli, while altered expression or mutational inactivation of PRDX1 associates with increased susceptibility to oxidative injury, cancer development, and inflammatory pathology. |
