{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HIF1AN (also known as factor inhibiting HIF‐1 or FIH‐1) is an oxygen‐dependent asparaginyl hydroxylase that plays a central role in the fine‐tuning of hypoxia‐inducible factor (HIF) signaling. Under normoxic conditions, FIH‐1 hydroxylates a conserved asparagine residue in the C‐terminal transactivation domain of HIF‐α subunits, thereby preventing their association with coactivators such as CBP/p300 and limiting HIF‐mediated transcription of target genes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In addition to this canonical role, FIH‐1 has been shown to differentially regulate the HIF‐α isoforms by exhibiting a higher affinity for HIF‐1α compared with HIF‐2α, thereby more potently dampening HIF‐1–driven gene expression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", and contributing to cell type–specific differences in hypoxic responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond regulation of HIF activity, FIH‐1 also hydroxylates the intracellular domain of Notch receptors at critical asparagine residues, thereby negatively modulating Notch signaling and influencing processes such as myogenic differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In the context of cancer and other pathologies, FIH‐1 function is further modulated by microRNAs. For example, in multiple myeloma–derived exosomes and in keratinocytes, microRNAs (miR‐135b and miR‐31, respectively) target FIH‐1 to suppress its expression, which leads to enhanced HIF activity and promotes angiogenesis or differentiation programs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Similarly, in prostate cancer cells, miR‐182 has been shown to directly target FIH‐1 (as well as PHD2) to relieve repression of HIF‐1α and thereby facilitate a robust hypoxic response that promotes angiogenesis and tumor growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Genetic studies in mice further underscore the broader physiological impact of FIH‐1. For instance, knockout models have revealed that loss of FIH‐1 results in marked metabolic alterations – including reduced body weight, elevated metabolic rate, and enhanced insulin sensitivity – indicating that FIH‐1 is a key regulator of systemic metabolism, likely acting in part via the nervous system."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Finally, proteomic analyses have uncovered that FIH‐1 can associate with other regulatory proteins such as the ubiquitin ligase E6AP, suggesting that FIH‐1/HIF1AN may participate in more complex cellular networks that extend beyond oxygen sensing."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings reveal that HIF1AN/FIH‐1 is a multifaceted regulator that integrates oxygen availability with transcriptional control of adaptive responses, Notch signaling, metabolic regulation, and angiogenesis. Its modulation by microRNAs and protein–protein interactions further expands its role as a critical node in both physiological processes and pathologies such as cancer.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "David Lando, Daniel J Peet, Jeffrey J Gorman, et al. 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