{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HEPHL1 is a multicopper ferroxidase that plays a central role in iron redox regulation and homeostasis. Its function has been implicated in diverse biological processes and disease contexts. For instance, in a mouse model of diaphragm hypoplasia, HEPHL1 was found to be one of several genes with markedly reduced expression in Fgfrl1‐null diaphragms, suggesting that proper iron handling via HEPHL1 may contribute to muscular and structural tissue development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In birds, transcriptome analysis of the uterus in Japanese quail revealed that HEPHL1 is strongly expressed in the wild‐type, where it is part of a suite of heme-biosynthesis–related genes. Its downregulation in quail with a white eggshell phenotype points to a role in regulating protoporphyrin IX accumulation, which is crucial for eggshell pigmentation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In humans, functional studies have demonstrated that HEPHL1’s ferroxidase activity is critical for maintaining proper iron distribution. Loss-of-function mutations in HEPHL1—as evidenced by a patient with abnormal hair characteristics (pili torti, trichorrhexis nodosa) and cognitive dysfunction—lead to intracellular iron accumulation and reduced activity of other copper-dependent enzymes such as lysyl oxidase. These findings were further corroborated using a Hephl1 knockout mouse model that exhibited a curly whiskers phenotype, underscoring its role in hair formation and neurological function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, in the context of plasma cell disorders such as POEMS syndrome, recurrent mutations in HEPHL1 have been identified, suggesting that alterations in its function might also contribute to disease pathogenesis in hematological settings."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In studies of hepatocarcinogenesis induced by microcystin-LR, HEPHL1 emerged as a key gene within a miRNA-mRNA network regulating cell cycle and transformation processes, further highlighting its potential involvement in liver tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its central role in iron metabolism, genetic investigations have implicated HEPHL1 in broader disease contexts. Candidate gene analyses in Parkinson’s disease have identified variants in HEPHL1, while epidemiological studies of colorectal neoplasia have shown that specific single nucleotide polymorphisms in HEPHL1 may modulate the impact of dietary iron intake on adenoma and cancer risk."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Overall, these findings point to HEPHL1 as a crucial enzyme that, through its ferroxidase activity, ensures proper iron oxidation and distribution. This activity is vital not only for cellular iron homeostasis but also for processes such as tissue development, pigment and hair formation, and potentially modulating disease susceptibility in diverse clinical settings.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nelson LopezJimenez, Simon Gerber, Vlad Popovici, et al. 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