{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FBXO28, a member of the F‐box protein family and a substrate recognition subunit of the SCF (Skp1–Cullin1–F‐box) E3 ubiquitin ligase complex, has emerged as a multifaceted regulator in diverse cellular contexts. In cancer, FBXO28 mediates non‐proteolytic ubiquitylation of the oncoprotein MYC, thereby enhancing MYC‐dependent transcription and promoting tumorigenesis, with high FBXO28 expression correlating with poor clinical outcome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the neurodevelopmental arena, genetic studies have implicated FBXO28 as a critical candidate gene; both microdeletions encompassing FBXO28 and de novo frameshift mutations are associated with intellectual disability, seizures, and developmental epileptic encephalopathies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "4"}]}, {"type": "t", "text": " FBXO28 also participates in the regulation of mitochondrial function through its role in the monoubiquitylation of the cardiolipin remodeling enzyme Alcat1, thereby modulating mitochondrial respiration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, its involvement in oncogenic gene rearrangements is underscored by the identification of a novel fusion between FBXO28 and ALK in a distinct melanocytic spindle cell tumor."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " The regulation of FBXO28 itself is dynamic, as its stability is controlled by the neddylation pathway and SCF‐mediated degradation mechanisms."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Beyond these roles, FBXO28 influences cell survival in specialized tissues; down‐regulation of FBXO28 compromises pancreatic β‐cell survival under diabetic conditions"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", while its up‐regulation in glomerular mesangial cells contributes to proliferative responses via interaction with TRAF6 and subsequent ERK5 activation in mesangioproliferative glomerulonephritis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, single nucleotide variants in the 3′ untranslated region of FBXO28 may alter mRNA structure and miRNA binding, potentially affecting protein production and contributing to the pathogenesis of mesial temporal lobe epilepsy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these studies highlight FBXO28 as a critical modulator of ubiquitin‐mediated signaling pathways with significant implications in tumor biology, neurodevelopment, mitochondrial integrity, and cell survival.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Diana Cepeda, Hwee-Fang Ng, Hamid Reza Sharifi, et al. 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