{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThioredoxin reductase 1 (TXNRD1) is an essential selenoprotein that catalyzes the NADPH‐dependent reduction of oxidized thioredoxin and other substrates, thereby maintaining cellular redox homeostasis. In addition to reducing the disulfide bonds in its primary substrate thioredoxin, TXNRD1 drives the reduction of ubiquinone‐10 to ubiquinol‐10—a reaction that regenerates a key lipophilic antioxidant—and supports a broad spectrum of redox processes via its unique C‐terminal –Gly–Cys–Sec–Gly active motif. Backup reducing systems such as glutathione and glutaredoxin can partially compensate when TXNRD1 activity falters, emphasizing its central role in cellular antioxidant defense."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn numerous human malignancies—including breast, lung, and hepatocellular carcinomas—TXNRD1 is frequently overexpressed and its elevated levels have been associated with aggressive tumor behavior and poor prognosis. Pharmacological targeting of TXNRD1 with electrophilic or redox‐active compounds such as curcumin, shikonin, gambogic acid, parthenolide, novel derivatives like B19, auranofin, and motexafin gadolinium has been shown to irreversibly inhibit its disulfide reduction activity. Such inhibition not only attenuates the enzyme’s antioxidant capacity but also converts TXNRD1 into an NADPH oxidase, thereby promoting the accumulation of reactive oxygen species that trigger mitochondrial dysfunction and apoptotic cell death. Moreover, these interventions modulate drug responses and enhance the efficacy of conventional anticancer therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "20"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTXNRD1 expression and activity are stringently regulated at the transcriptional level—often via antioxidant response elements in its promoter—to ensure dynamic control of cellular redox signaling. Perturbations such as selenium deficiency or electrophilic targeting can compromise the key selenocysteine in TXNRD1, resulting in “SecTRAPs” (selenium‐compromised TXNRD1–derived apoptotic proteins) that, despite lacking normal reductase activity, acquire pro‐oxidant NADPH oxidase functions. In addition, TXNRD1 modulates key signaling cascades by affecting transcription factors including p53, AP-1, and NF-κB, and even participates in the regulation of HIV-1 Tat activity in macrophages. These diverse roles position TXNRD1 as a critical node in both physiological redox regulation and the pathological processes associated with oxidative stress, inflammation, and tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "27"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stephan Gromer, Jurgen H Gross "}, {"type": "b", "children": [{"type": "t", "text": "Methylseleninate is a substrate rather than an inhibitor of mammalian thioredoxin reductase. Implications for the antitumor effects of selenium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109234200"}], "href": "https://doi.org/10.1074/jbc.M109234200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11782468"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11782468"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Shervin Karimpour, Junyang Lou, Lilie L Lin, et al. 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