{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPirin is a highly conserved nuclear nonheme iron‐binding protein belonging to the cupin superfamily. Early structural and biochemical studies have demonstrated that PIR interacts with key transcriptional regulators—including Bcl‐3 and nuclear factor I—to modulate NF‑κB–driven gene transcription. Such interactions implicate pirin as a transcriptional coregulator essential for fine‐tuning diverse gene expression programs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its regulatory role, pirin exhibits enzymatic activity. Structural investigations have revealed that both bacterial and human forms of pirin possess quercetinase activity, suggesting that pirin may function in redox reactions. Notably, changes in the redox state of its iron cofactor induce distinct conformational shifts that affect its interaction with transcription factors, thereby allowing pirin to serve as a redox sensor in the nucleus."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther, pirin influences cellular behavior linked to migration and phenotypic plasticity. Functional studies in melanoma models and epithelial cells have shown that modulation of pirin expression can affect cell migration and epithelial-to-mesenchymal transition (EMT), including the suppression of E‑cadherin expression. In melanocytic cells, pirin appears to play a role in overcoming senescence, thereby potentially linking its activity to processes that enable cancer progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMore recently, pirin has been implicated in the regulation of cell death modalities. In studies focused on ferroptosis—a distinct, iron-dependent form of regulated cell death—upregulation of pirin has been shown to mediate resistance to ferroptotic stress. Through facilitating proper binding of NF‑κB proteins to target genes and limiting oxidative DNA damage (thereby reducing HMGB1 release and subsequent autophagy activation), pirin emerges as a pivotal factor in orchestrating the cellular response to oxidative stress in cancer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hai Pang, Mark Bartlam, Qinghong Zeng, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Pirin delocalization in melanoma progression identified by high content immuno-detection based approaches."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2121-11-5"}], "href": "https://doi.org/10.1186/1471-2121-11-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20089166"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20089166"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kamil Brzóska, Tomasz M Stępkowski, Marcin Kruszewski "}, {"type": "b", "children": [{"type": "t", "text": "Basal PIR expression in HeLa cells is driven by NRF2 via evolutionary conserved antioxidant response element."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biochem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11010-013-1931-0"}], "href": "https://doi.org/10.1007/s11010-013-1931-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24390086"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24390086"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Melanie Adams, Zongchao Jia "}, {"type": "b", "children": [{"type": "t", "text": "Structural and biochemical analysis reveal pirins to possess quercetinase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M501034200"}], "href": "https://doi.org/10.1074/jbc.M501034200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15951572"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15951572"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Fange Liu, Imran Rehmani, Shingo Esaki, et al. 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