{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPeroxiredoxin 4 (PRDX4) is a unique member of the peroxiredoxin family that is localized to the endoplasmic reticulum (ER) where it plays a central role in regulating oxidative protein folding and redox homeostasis. In the ER, PRDX4 efficiently degrades hydrogen peroxide produced by oxidoreductases such as Ero1 and, in doing so, couples peroxide removal with the oxidation of protein disulfide isomerases (PDIs) to promote disulfide‐bond formation in nascent proteins. Detailed structural studies have revealed that PRDX4 assembles into a stable decameric (toroid‐shaped) structure and undergoes conformational transitions upon oxidation (sulfenylation) of its active site cysteine, which is critical for its catalytic cycle yet also renders it susceptible to hyperoxidation under high peroxide flux. Notably, interactions with specific ER chaperones and retention factors (for example, via disulfide exchange with ERp44) ensure that PRDX4 remains within the ER lumen to continuously support oxidative protein folding while limiting oxidative stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its fundamental biochemical role in the ER, aberrant PRDX4 expression and function have been linked to a wide spectrum of human diseases and cell‐signaling abnormalities. In diverse cancer settings—including breast, prostate, lung, oral squamous cell, pancreatic, and hematological malignancies—PRDX4 not only contributes to redox regulation but also modulates signaling pathways that control proliferation, apoptosis, metastasis, and even therapeutic drug clearance. In some tumors the PRDX4 axis, by interacting with partners such as sulfiredoxin or affecting receptor signaling (for example through interactions with the granulocyte colony‐stimulating factor receptor and other cell‐surface receptors), promotes tumor growth and invasiveness, while in other contexts its downregulation or hyperoxidation is associated with increased cellular damage. Moreover, altered PRDX4 levels have been observed in conditions ranging from metabolic and cardiovascular disorders (including type 2 diabetes, insulin secretory defects, and post‐cardiac arrest syndromes) to inflammatory states (such as rheumatoid arthritis, cholestatic liver injury, silicosis, and acute pancreatitis) as well as in reproductive disorders like preeclampsia and recurrent pregnancy loss. These clinical findings not only suggest that PRDX4 may serve as a valuable prognostic or diagnostic biomarker but also point to its potential as a therapeutic target in diseases where oxidative stress and redox imbalance are key contributors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "49"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chuanlu Shen, Carl Nathan "}, {"type": "b", "children": [{"type": "t", "text": "Nonredundant antioxidant defense by multiple two-cysteine peroxiredoxins in human prostate cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12080185"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12080185"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Timothy J Tavender, Alyson M Sheppard, Neil J Bulleid "}, {"type": "b", "children": [{"type": "t", "text": "Peroxiredoxin IV is an endoplasmic reticulum-localized enzyme forming oligomeric complexes in human cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20071428"}], "href": "https://doi.org/10.1042/BJ20071428"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18052930"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18052930"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yan Ding, Sohsuke Yamada, Ke-Yong Wang, et al. 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