{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZFHX3 (also known as ATBF1) is emerging as a master regulator that orchestrates a wide array of biological processes. In the central nervous system, it modulates circadian rhythms by controlling the transcription of neuropeptides in the suprachiasmatic nucleus, and its dysfunction leads to alterations in sleep behavior and light entrainment. Moreover, ZFHX3 has been implicated in neuronal survival pathways, linking DNA damage responses with CREB‐mediated transcription and, possibly, retinal function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in the brain, ZFHX3 is a critical regulator of cell differentiation and tissue homeostasis. It governs endocrine and epithelial differentiation during organogenesis – for example, by controlling pituitary enhancer activity as well as mammary gland development via maintenance of prolactin receptor signaling. In the prostate, loss of ZFHX3 leads to hyperplasia and neoplastic changes likely owing to altered expression of secretory and membrane proteins, highlighting its importance as a tumor suppressor in multiple tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nZFHX3 also plays an important role in the heart and arrhythmogenesis. Its expression in atrial cells influences electrophysiological properties and calcium homeostasis, while its loss-of-function is associated with atrial fibrillation through mechanisms that involve dysregulation of inflammatory STAT3 signaling and altered microRNA profiles. These findings suggest that ZFHX3 deficiency may contribute to cardiac rhythm disturbances and, hence, represent a novel molecular target in arrhythmia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn developmental contexts within the nervous system, ZFHX3 is essential for the proper differentiation and survival of neuronal subtypes. For example, in the striatum it is selectively expressed in the progenitors of D1 medium spiny neurons, and its loss disrupts late neuronal generation. In addition, post‐translational regulation of ZFHX3 – through phosphorylation that protects it from calpain‐1–mediated degradation – underscores its tightly controlled stability during neurodevelopment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond neural tissues, ZFHX3 influences systemic energy balance and structural physiology. In the hypothalamus, its mutation alters the expression of key neuropeptides, impacting food intake, growth, and metabolic expenditure. Moreover, its function extends to modulating immune gene programs in alveolar macrophages exposed to hypercapnia and to regulating bone formation. In osteoblasts, deletion of ZFHX3 diminishes trabecular bone mass and alters the transcription of osteoblast-specific genes, revealing its multifaceted role in maintaining tissue integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael J Parsons, Marco Brancaccio, Siddharth Sethi, et al. 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