{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMyo‐inositol oxygenase (MIOX) is a non‐heme iron enzyme that catalyzes the oxidative ring cleavage of myo‐inositol to yield d‐glucuronic acid—the first and rate‐limiting step in the sole pathway of myo‐inositol catabolism. Its activity has been well characterized in kidney tissue, where cloning studies in pig, mouse, rat, and human have established a highly conserved 33 kDa enzyme with defined kinetic parameters. This biochemical activity not only serves as a key step in intracellular phosphoinositide regulation but also links metabolic flux through the myo‐inositol pathway to cellular redox balance."}, {"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": "\nMultiple studies have revealed that the expression and activity of MIOX are tightly regulated by metabolic and nutritional cues. In renal tubular cells, exposure to polyols, high glucose, fatty acids, and osmotic stress induces transcriptional activation of MIOX by promoter elements—such as osmotic response elements and sterol regulatory elements—and is further modulated via epigenetic mechanisms, including promoter hypomethylation and increased binding of transcription factors like Sp1. These regulatory processes contribute to elevated MIOX activity, which in turn leads to increased reactive oxygen species (ROS) generation, perturbation of NADPH and glutathione levels, and ultimately, cellular injury."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of diabetic nephropathy, MIOX up‐regulation appears to be a pivotal contributor to tubular injury. Enhanced enzyme expression under hyperglycemic conditions, as well as genetic polymorphisms in the MIOX gene, have been associated with increased oxidative stress, ER stress, and fibrotic responses in renal tubules. These findings have spurred interest in using MIOX as a potential biomarker for early detection of tubular damage in diabetic nephropathy, although further studies are required to validate its clinical utility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDivergent roles of MIOX have also been observed in cancer. In tumor models, particularly hepatocellular carcinoma and clear cell renal cell carcinoma (ccRCC), MIOX plays a dual role depending on its regulation and tissue context. In one study, the long noncoding RNA NEAT1 promoted MIOX expression via a miRNA-dependent mechanism to enhance ROS production and sensitize tumor cells to ferroptosis—thereby increasing the efficacy of ferroptosis inducers. Conversely, in ccRCC, MIOX expression is markedly down-regulated in tumor epithelial cells and its experimental re-expression inhibits proliferation and metastasis by modulating ROS levels and suppressing pathways such as STAT3/c-Myc-mediated epithelial-mesenchymal transition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its renal and oncologic implications, MIOX has been implicated in other systemic conditions. In sepsis-induced cardiac dysfunction, for example, MIOX may exert pro-inflammatory effects that exacerbate cardiac injury. By contrast, in polycystic ovary syndrome (PCOS), studies have shown that serum MIOX levels remain unaltered, suggesting that the observed myo-inositol deficiency in PCOS is not due to changes in MIOX activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "R J Arner, K S Prabhu, J T Thompson, et al. 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