{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNR1D2, which encodes the nuclear receptor Rev‐Erbβ, functions as a heme‐binding transcriptional repressor that is central to the regulation of circadian rhythms, metabolism, and inflammatory signaling. Binding of heme—with its affinity modulated by the protein’s redox state and specific heme regulatory motifs—facilitates the recruitment of co‐repressors (e.g., NCoR1) to target promoters such as those controlling BMAL1 expression, thereby linking cellular metabolic status with the molecular clock. In addition, studies using metalloporphyrin analogs have revealed that subtle changes at the metal center can switch ligand activity between agonism and antagonism, while gas molecules like CO/NO further modulate the redox potential and function of Rev‐Erbβ."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn several cancer contexts, including breast cancer and glioblastoma, NR1D2 is frequently overexpressed and has been shown to influence tumor cell behavior. Its activity modulates key oncogenic pathways such as the PI3K/AKT cascade—partly through transcriptional regulation of targets like the receptor tyrosine kinase AXL—and can determine cellular sensitivity to autophagy inhibitors like chloroquine. Moreover, NR1D2’s ability to recruit or interact with chromatin‐modifying factors (for example, Tip60 and HDAC1 in the regulation of apolipoprotein genes) suggests that its deregulation may contribute to both altered lipid metabolism and the metabolic risk profiles seen in type 2 diabetes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in circadian and metabolic regulation as well as in cancer, NR1D2 significantly impacts inflammatory and host‐pathogen processes. In astroglial cells, activation of Rev‐Erbβ helps suppress the transcription of inflammatory mediators such as MMP-9 and CCL2, thereby modulating the neuroinflammatory response. Furthermore, microRNA-210 can downregulate NR1D2 expression in conditions like cryptorchidism, linking its deregulation to reproductive pathologies. Finally, NR1D2 has emerged as a critical regulator of host lipid metabolism, where its activity can impair autophagic flux during infections by pathogens such as Burkholderia pseudomallei and Plasmodium species, thus shaping the cellular environment in favor of pathogen proliferation. Transcriptomic analyses also highlight isoform-selective roles for Rev-Erbβ in pathways including extracellular matrix regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Srilatha Raghuram, Keith R Stayrook, Pengxiang Huang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Structure of REV-ERBβ ligand-binding domain bound to a porphyrin antagonist."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.545111"}], "href": "https://doi.org/10.1074/jbc.M113.545111"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24872411"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24872411"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Anindita Sarkar, Eric L Carter, Jill B Harland, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Dual inhibition of REV-ERBβ and autophagy as a novel pharmacological approach to induce cytotoxicity in cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2014.203"}], "href": "https://doi.org/10.1038/onc.2014.203"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25023698"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25023698"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Min Yu, Wenjing Li, Qianqian Wang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Human nuclear hormone receptor activity contributes to malaria parasite liver stage development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Chem Biol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.chembiol.2023.04.011"}], "href": "https://doi.org/10.1016/j.chembiol.2023.04.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37172592"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37172592"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Hana Cho, Ahee Yun, Joohee Kim, et al. 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