{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ADHFE1 is an iron‐containing, mitochondrial alcohol dehydrogenase with multifaceted roles in human metabolism that vary with tissue context and disease state. In breast tumors, ADHFE1 functions as an oncogene by catalyzing the conversion of substrates into D‐2‑hydroxyglutarate (D‑2HG), a known oncometabolite. Enhanced D‑2HG production by ADHFE1 has been linked to MYC‐driven metabolic reprogramming, increased reactive oxygen species, altered glutamine utilization, and epigenetic modifications that collectively promote dedifferentiation and tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Similarly, in clear cell renal cell carcinoma, decreased HSP60 expression leads to disrupted mitochondrial complex integrity and elevated reactive oxygen species that favor Fe–S cluster fragmentation; this, in turn, upregulates ADHFE1 expression and further enhances 2‑HG production, thereby contributing to tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In contrast, ADHFE1 expression is frequently silenced in certain epithelial cancers through aberrant promoter hypermethylation. In oral squamous cell carcinoma, retinoid signaling–related genes including ADHFE1 are downregulated via a mechanism involving deregulated microRNAs and elevated DNMT3B levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In colorectal cancer, multiple studies have demonstrated that ADHFE1 is hypermethylated and its expression markedly reduced. Such epigenetic suppression correlates with poor differentiation, enhanced cell proliferation, and loss of differentiation markers, while restoration of ADHFE1 expression promotes differentiated phenotypes and cell cycle arrest."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in cancer, ADHFE1 is expressed in non‐malignant tissues where it may contribute to specialized metabolic processes. In neuronal cell models, ADHFE1 transcript presence suggests a role in γ‑hydroxybutyrate metabolism via hydroxyacid–oxoacid transhydrogenase activity that is reminiscent of bacterial dehydrogenases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In adipocytes, ADHFE1 displays differentiation‐dependent expression and appears to participate in energy metabolism, potentially linking its function to adipose tissue homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, molecular cloning studies in human fetal brain have identified ADHFE1 as a distinct, iron‐activated enzyme with tissue‑specific expression patterns, further underscoring its specialized metabolic functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings highlight a context‑dependent dualism of ADHFE1: while its upregulation and resultant D‑2HG production can drive oncogenic metabolic reprogramming in breast and renal cancers, epigenetic silencing of ADHFE1 in colorectal and oral cancers may disrupt normal differentiation processes. In addition, ADHFE1’s expression in neuronal and adipose tissues points to broader roles in energy and neurotransmitter metabolism. Further elucidation of ADHFE1’s regulatory mechanisms may provide valuable insights into its potential as both a diagnostic biomarker and a therapeutic target.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Prachi Mishra, Wei Tang, Vasanta Putluri, et al. 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