{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMLXIP, which encodes the transcription factor MondoA, functions as a nutrient sensor that detects intracellular glucose metabolites—most notably glucose‐6‐phosphate—and thereby governs a critical metabolic feedback loop. In resting cells, MondoA is tethered at the outer mitochondrial membrane; when glucose or analogous hexoses (and even conditions such as acidosis) elevate glucose‐6‐phosphate levels, MondoA shuttles to the nucleus and directly activates genes (for example, thioredoxin-interacting protein [TXNIP] and key glycolytic enzymes) that subsequently act to restrain glucose uptake. This multi‐step regulation requires both hexokinase activity and additional signals that enable promoter occupancy and coactivator recruitment, thus integrating mitochondrial energy status with nuclear gene expression."}, {"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": "\nBeyond maintaining energy homeostasis in normal tissues, MLXIP plays a pivotal role in metabolic reprogramming during oncogenesis and in settings of nutrient excess. MondoA collaborates with oncogenic drivers—such as Myc—to reprogram pathways that encompass lipid biosynthesis, oxidative phosphorylation, and insulin signaling. Studies in acute lymphoblastic leukemia, cervical cancer, and even in specialized immune subsets like intratumoral regulatory T cells have revealed that aberrant expression of MondoA fosters enhanced glycolysis and survival under metabolic stress. Moreover, its activity is modulated by key intracellular signals including mTOR, which can restrict or permit nuclear accumulation and transcriptional activity. Such molecular interplay underscores the therapeutic potential of targeting MLXIP‐directed circuits in a range of malignancies and metabolic disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPhylogenomic analyses further underscore the evolutionary conservation of MLXIP, indicating that MondoA mediates an ancient and fundamental role in glucose metabolism across vertebrates. In broader clinical contexts, investigations of related transcriptional networks have associated polymorphisms in MLXIPL—as well as alterations in MLXIP expression—with phenotypes ranging from coronary artery disease to hip osteoarthritis, suggesting that the regulatory functions of these networks extend into cardiovascular and musculoskeletal health."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alanna L Eilers, Eleanor Sundwall, Monica Lin, et al. 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