{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNFKBIA, the gene encoding the key inhibitory protein IκBα, is central to the regulation of the nuclear factor‐kappaB (NF‐κB) pathway. In resting cells, IκBα masks the nuclear localization signals of NF‐κB dimers to retain them in the cytoplasm, whereas various stimuli—including metabolic, oxidative, and inflammatory signals—induce post‐translational modifications (such as phosphorylation, ubiquitination, nitration, and hydroxylation) that trigger IκBα’s degradation and thus release NF‐κB for nuclear translocation and gene transcription. This dynamic regulation is highlighted in studies where decreased IκBα levels correlate with lipid‐induced insulin resistance, and where glucose challenges reduce IκBα protein in mononuclear cells, thereby promoting NF‐κB activation (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic and epigenetic evidence further underscores the immunological and oncological ramifications of NFKBIA regulation. Genome‐wide association studies have implicated variants in or near NFKBIA in psoriasis susceptibility, while meta‐analyses and studies of gene deletions have identified alterations in NFKBIA that associate with inflammatory disorders and promote tumorigenesis in glioblastoma. Moreover, mutations affecting critical residues, such as a serine‐to‐alanine change at position 32, lead to immunodeficiency syndromes resembling hyper immunoglobulin M–like disease (refer to."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIκBα function is further refined by complex regulation at both the transcriptional and post‐translational levels. Its promoter activity is modulated by the dynamic recruitment of coactivators and corepressors, which dictates the magnitude and duration of NF‐κB responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Post‐translational modifications—such as the tyrosine phosphorylation observed upon H₂O₂ treatment that promotes NF‐κB activation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", hydroxylation by factor inhibiting HIF to modify ankyrin repeat domains"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and nitration at Tyr181 under UV irradiation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "—add additional layers of control. Notably, in certain contexts, IκBα regulation is bypassed or modified, as seen with p65 phosphorylation at Ser536 that occurs independently of IκBα binding."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Structural studies further reveal that inherent conformational flexibility in IκBα allows regions of the protein to fold upon binding NF‐κB, thereby fine‐tuning its inhibitory capacity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional cellular contexts illustrate the diverse roles of IκBα. In endothelial and neuronal cells, for example, factors such as HSP27 or secretory clusterin have been shown to enhance IκBα degradation—thereby activating NF‐κB and contributing to pro‐inflammatory and pro-survival gene expression in diseases including cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Conversely, agents like 20‐hydroxycholecalciferol or Nur77 upregulate IκBα expression, attenuating NF‐κB activity and offering cytoprotective effects against inflammation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " In astrocytes, expression of a dominant negative form of IκBα promotes a more favorable milieu for neural recovery after injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Moreover, natural compounds such as α-mangostin have been shown to prevent IκBα degradation and thus reduce metastatic traits in cancer cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": ", while in neutrophils, the nuclear accumulation of IκBα is linked to enhanced apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these findings emphasize that NFKBIA/IκBα serves as a master regulator of NF‐κB signaling, with its tightly controlled expression, modification, and degradation governing cellular outcomes across metabolic, inflammatory, and oncogenic processes. The integration of signals via IκBα not only directs the tempo and extent of NF‐κB–dependent transcription but also influences cell fate decisions, thereby providing promising avenues for therapeutic intervention in conditions such as insulin resistance, chronic inflammation, cancer, and immunodeficiency."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "26"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Samar I Itani, Neil B Ruderman, Frank Schmieder, et al. 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